Beta lactam antibiotic monotherapy versus beta lactamaminoglycoside antibiotic combination therapy for sepsis (Review) Paul M, Grozinsky S, Soares-Weiser K, Leibovici L
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2009, Issue 1 http://www.thecochranelibrary.com
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Monotherapy versus combination therapy, Outcome 1 All cause fatality. . . . . . . Analysis 1.2. Comparison 1 Monotherapy versus combination therapy, Outcome 2 All cause fatality by study groups. Analysis 1.3. Comparison 1 Monotherapy versus combination therapy, Outcome 3 All cause fatality (Gram negative infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Monotherapy versus combination therapy, Outcome 4 All cause fatality (Gram negative bacteremia). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 Monotherapy versus combination therapy, Outcome 5 All cause fatality (non urinary tract infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.1. Comparison 2 Monotherapy versus combination therapy, Outcome 1 Clinical failure. . . . . . . Analysis 2.2. Comparison 2 Monotherapy versus combination therapy, Outcome 2 Clinical failure by study groups. . Analysis 2.3. Comparison 2 Monotherapy versus combination therapy, Outcome 3 Bacteriological failure - all. . . Analysis 2.4. Comparison 2 Monotherapy versus combination therapy, Outcome 4 UTI relapse or re-infection. . . Analysis 2.5. Comparison 2 Monotherapy versus combination therapy, Outcome 5 Clinical failure (Gram negative infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.6. Comparison 2 Monotherapy versus combination therapy, Outcome 6 Clinical failure (Gram negative bacteremia). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.7. Comparison 2 Monotherapy versus combination therapy, Outcome 7 Clinical failure (Pseudomonas aeruginosa infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.8. Comparison 2 Monotherapy versus combination therapy, Outcome 8 Clinical failure (bacteremia). . . Analysis 2.9. Comparison 2 Monotherapy versus combination therapy, Outcome 9 Clinical failure (urinary tract infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.10. Comparison 2 Monotherapy versus combination therapy, Outcome 10 Clinical failure (non urinary tract infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.1. Comparison 3 Monotherapy versus combination therapy, Outcome 1 Bacterial superinfections. . . . Analysis 3.2. Comparison 3 Monotherapy versus combination therapy, Outcome 2 Fungal superinfections. . . . . Analysis 3.3. Comparison 3 Monotherapy versus combination therapy, Outcome 3 Bacterial colonization. . . . . Analysis 3.4. Comparison 3 Monotherapy versus combination therapy, Outcome 4 Fungal colonization. . . . . . Analysis 3.5. Comparison 3 Monotherapy versus combination therapy, Outcome 5 Bacterial colonization - surveillance cultures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.6. Comparison 3 Monotherapy versus combination therapy, Outcome 6 Bacterial resistance development. Analysis 4.1. Comparison 4 Monotherapy versus combination therapy, Outcome 1 Any adverse event. . . . . . Analysis 4.2. Comparison 4 Monotherapy versus combination therapy, Outcome 2 Adverse events requiring treatment discontinuation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 4.3. Comparison 4 Monotherapy versus combination therapy, Outcome 3 Any nephrotoxicity. . . . . . Analysis 5.1. Comparison 5 Monotherapy versus combination therapy, Outcome 1 Drop-outs for all cause fatality. . Analysis 5.2. Comparison 5 Monotherapy versus combination therapy, Outcome 2 Drop-outs for clinical failure. . . Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Analysis 6.1. Comparison 6 Monotherapy versus combination therapy, Outcome 1 All cause fatality (Gram positive infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 6.2. Comparison 6 Monotherapy versus combination therapy, Outcome 2 Clinical failure (Gram positive infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 6.3. Comparison 6 Monotherapy versus combination therapy, Outcome 3 Bacteriological failure (Gram positive infections). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 6.4. Comparison 6 Monotherapy versus combination therapy, Outcome 4 Need for operation (endocarditis). Analysis 7.1. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 1 All cause fatality by allocation concealment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 7.2. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 2 All cause fatality by allocation generation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 7.3. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 3 All cause fatality by ITT vs. per-protocol analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 7.4. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 4 Clinical failure by allocation concealment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 7.5. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 5 Clinical failure by allocation generation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 7.6. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 6 Clinical failure by blinding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 7.7. Comparison 7 Monotherapy versus combination therapy (sensitivity analyses), Outcome 7 Clinical failure by ITT versus per-protocol analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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[Intervention Review]
Beta lactam antibiotic monotherapy versus beta lactamaminoglycoside antibiotic combination therapy for sepsis Mical Paul1 , Simona Grozinsky2 , Karla Soares-Weiser3 , Leonard Leibovici4 1 Infectious
Diseases Unit and Department of Medicine E, Rabin Medical Center, Petah-Tikva, Israel. 2 Internal Medicine E, Rabin Medical Center, Petah-Tikva, Israel. 3 Enhance Reviews, Kfar-Saba, Israel. 4 Department of Medicine E, Beilinson Campus, Rabin Medical Center, Petah-Tiqva, Israel Contact address: Mical Paul, Infectious Diseases Unit and Department of Medicine E, Rabin Medical Center, Beilinson Campus, Petah-Tikva, 49100, Israel.
[email protected]. (Editorial group: Cochrane Anaesthesia Group.) Cochrane Database of Systematic Reviews, Issue 1, 2009 (Status in this issue: Edited) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DOI: 10.1002/14651858.CD003344.pub2 This version first published online: 25 January 2006 in Issue 1, 2006. Re-published online with edits: 21 January 2009 in Issue 1, 2009. Last assessed as up-to-date: 10 November 2005. (Help document - Dates and Statuses explained) This record should be cited as: Paul M, Grozinsky S, Soares-Weiser K, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD003344. DOI: 10.1002/14651858.CD003344.pub2.
ABSTRACT Background Optimal antibiotic treatment for sepsis is imperative. Combining a beta-lactam antibiotic with an aminoglycoside antibiotic may have certain advantages over beta-lactam monotherapy. Objectives We compared clinical outcomes for beta lactam-aminoglycoside combination therapy versus beta lactam monotherapy for sepsis. Search strategy We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2004); MEDLINE (1966 to July 2004); EMBASE (1980 to March 2003); LILACS (1982 to July 2004); and conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (1995 to 2003). We scanned citations of all identified studies and contacted all corresponding authors. Selection criteria We included randomized and quasi-randomized trials comparing any beta-lactam monotherapy to any combination of one beta-lactam and one aminoglycoside for sepsis. Data collection and analysis The primary outcome was all-cause fatality. Secondary outcomes included treatment failure, superinfections, colonization, and adverse events. Two authors independently collected data. We pooled relative risks (RR) with their 95% confidence intervals (CI) using the fixed effect model. We extracted outcomes by intention-to-treat analysis whenever possible. Main results We included 64 trials, randomizing 7586 patients. Twenty trials compared the same beta-lactam in both study arms, while the remaining compared different beta-lactams using a broader spectrum beta-lactam in the monotherapy arm. In studies comparing the same betaBeta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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lactam, we observed no difference between study groups with regard to all-cause fatality, RR 1.01 (95% CI 0.75-1.35) and clinical failure, RR 1.11 (95% CI 0.95-1.29). In studies comparing different beta-lactams, we observed an advantage to monotherapy: all cause fatality RR 0.85 (95% CI 0.71-1.01), clinical failure RR 0.77 (95% CI 0.69-0.86). No significant disparities emerged from subgroup and sensitivity analyses, including the assessment of patients with Gram-negative and Pseudomonas aeruginosa infections. We detected no differences in the rate of resistance development. Adverse events rates did not differ significantly between the study groups overall, although nephrotoxicity was significantly more frequent with combination therapy, RR 0.30 (95% CI 0.23-0.39). We found no heterogeneity for all comparisons. We included a small subset of studies addressing patients with Gram-positive infections, mainly endocarditis. We identified no difference between monotherapy and combination therapy in these studies. Authors’ conclusions The addition of an aminoglycoside to beta-lactams for sepsis should be discouraged. All-cause fatality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity.
PLAIN LANGUAGE SUMMARY Single versus combination antibiotic treatment for severe infections: beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy Infections caused by bacteria are a leading cause of preventable death. The mortality associated with severe infections necessitating hospitalization is about 30%. Antibiotic treatment improves survival. There are several classes of antibiotics currently in use. The beta-lactam class is one of the most important class in use. Antibiotics belonging to it (penicillins, cephalosporins, and others) kill bacteria by disrupting their cell wall. Aminoglycosides (e.g. gentamicin) act though a different mechanism, inhibiting bacterial protein synthesis. Studies of bacteria in cell cultures have shown that combining a beta-lactam with an aminoglycoside results in bacterial killing superior to the simple additive activity of each of these antibiotics alone, a phenomenon termed ’synergism’. In humans, combination therapy may have several drawbacks, such as an increased rate of adverse effects. We therefore decided to compile clinical studies that compared treatment with a beta-lactam to treatment with a beta-lactam plus an aminoglycoside. Our objective was to assess whether combination treatment results in better outcomes, mainly survival. The review included 64 trials randomizing 7586 patients. Patients were hospitalized with urinary tract, intra-abdominal, skin and soft tissue infections, pneumonia, and infection of unknown origin. Antibiotics were administered intravenously. Combination antibiotic treatment did not improve the clinical efficacy achieved with the beta-lactam antibiotic alone. One set of studies compared a new, broad-spectrum beta-lactam to an older, less potent beta-lactam combined with an aminoglycoside (44 studies). In these studies, mortality and failure were lower with single beta-lactam antibiotic treatment. Mortality was reduced by 15%, but the difference was not statistically significant. The other set of studies compared one beta-lactam to the same beta-lactam combined with an aminoglycoside (20 studies). In these trials, no differences between single and combination antibiotic treatment were seen. The relative risk for mortality was 1.01, denoting equivalence of the two regimens. Adverse events rates did not differ between the study groups, overall, but renal damage was more frequent with combination therapy. Combination therapy did not prevent the development of secondary infections. The reviewers conclude that beta-lactam-aminoglycoside combination therapy offers no advantage to beta-lactams alone. Furthermore, combination therapy is associated with an increased risk of renal damage. Paucity of trials comparing the same beta-lactam in both study arms and incompleteness of mortality reporting may limit these conclusions. These results may not apply to locations in which resistance rates to narrow-spectrum beta-lactams are very low, such as Scandinavian counties.
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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BACKGROUND Sepsis is defined as the clinical evidence of infection, accompanied by a systemic inflammatory response such as fever. When associated with organ dysfunction, decreased blood flow in an organ (hypoperfusion), or abnormally low blood pressure (hypotension), sepsis is defined as severe (Bone 1992; Mandell 2004). Sepsis may be a response to direct microbial invasion or may be elicited by microbial signal molecules or toxin production. Infections may be lethal, with fatality rates ranging from less than 10% to more than 40% for those with severe sepsis (Moore 2001; Rangel-Frausto 1995; Russell 2000). Appropriate empirical antibiotic treatment, administered to the patient before identification of the pathogen or its antibiotic susceptibilities, has been shown to halve the fatality associated with sepsis (Bryant 1971; Ibrahim 2000; Leibovici 1998; Whitelaw 1992). Regimens recommended for the empirical treatment of sepsis include: (1) a single broad-spectrum agent, commonly from the beta lactam class of antibiotics; and (2) a combination of a beta lactam antibiotic with an aminoglycoside antibiotic (Mandell 2004). Combination antibiotic therapy has several theoretical advantages. First, it may have a broader antibiotic spectrum. Second, the combination may possess an enhanced potential (synergism), when compared to the additive effect of each of the antibiotics assessed separately (Giamarellou 1986; Klastersky 1982). Third, combination therapy has been claimed to suppress the emergence of subpopulations of microorganisms resistant to the antibiotics (Allan 1985; Milatovic 1987). The disadvantages of combination therapy may include additional costs, enhanced drug toxicity, the possible induction of resistance caused by the broader antibiotic spectrum (Manian 1996; Weinstein 1985), and possible antagonism between specific drug combinations (Moellering 1986). Aminoglycoside antibiotics are most active against Gram-negative bacteria (Mandell 2004). In addition, synergism between beta lactam antibiotics and aminoglycoside antibiotics has been repeatedly shown in vitro specifically for Gram-negative bacteria (Giamarellou 1986; Klastersky 1976; Klastersky 1982). Consequently, the benefit of combination therapy, if existent, may be more prominent in patients with Gram-negative infections. Other features related to the infection may affect prognosis. These include the site of infection and the specific causative pathogen. For example, infections caused by Pseudomonas aeruginosa have been shown to portend a poor prognosis (Baine 2001; Geerdes 1991; Leibovici 1997). We expect to deal with factors such as these, expected to underlie heterogeneity, using subgroup analysis where appropriate. Specific guidelines have been instituted for the empirical treatment of cancer patient with neutropenia, basing the suspicion of sepsis on fever alone (Hughes 2002). The authors have therefore considered studies addressing these patients in a separate review (Paul 2001). Numerous studies have been conducted comparing beta lactam monotherapy to beta lactam-aminoglycoside combination ther-
apy in patients with suspected or proven bacterial infections. Some trials have focused specifically on infections commonly caused by Gram-negative bacteria, such as urinary tract infections and hospital acquired infections, where the benefit of combination therapy may be more prominent. Nevertheless, superiority of either monotherapy or combination therapy has not been shown conclusively in these studies.
OBJECTIVES Our objectives were: 1. to compare beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy in patients with sepsis; and 2. to estimate the rate of adverse effects with each treatment regimen, including the development of bacterial resistance to antibiotics.
METHODS Criteria for considering studies for this review Types of studies We included randomized or quasi-randomized controlled trials. Types of participants We included hospitalized patients with sepsis acquired either in the community or in the hospital (nosocomial). We defined sepsis as clinical evidence of infection, plus evidence of a systemic response to infection (Bone 1992). We excluded neonates and preterm babies. We also excluded studies including more than 15% neutropenic patients. Types of interventions We considered studies comparing the antibiotic regimens described below. 1. Any intravenous beta-lactam antibiotic given as monotherapy, including: i) penicillins; ii) beta lactam drugs plus beta lactamase inhibitors (eg co-amoxiclav); iii) cephalosporins (eg ceftazidime, cefotaxime); iv) carbapenems (eg imipenem, meropenem). 2. Combination therapy of a beta lactam antibiotic (as specified) with one of the following aminoglycoside antibiotics: i) gentamicin; ii) tobramycin; iii) amikacin; iv) netilmicin;
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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v) streptomycin; vi) isepamicin; vii) sisomicin. Types of outcome measures Primary outcomes
All-cause fatality by the end of the study follow-up. Secondary outcomes
1. Treatment failure defined as death and/or one or more serious morbid events (persistence, recurrence, or worsening of clinical signs or symptoms of presenting infection; any modification of the assigned empirical antibiotic treatment; or any therapeutic invasive intervention required not defined in the protocol). 2. Length of hospital stay. 3. Dropouts: number of patients excluded from the outcome assessment after randomization. 4. Superinfection: recurrent infections defined as new, persistent, or worsening symptoms and/or signs of infection associated with the isolation of a new pathogen (different pathogen, or same pathogen with different susceptibilities) or the development of a new site of infection. 5. Colonization by resistant bacteria: the isolation of bacteria resistant to the beta lactam antibiotic, during or following antibiotic therapy, with no signs or symptoms of infection. 6. Adverse effects: i) life-threatening or associated with permanent disability (severe nephrotoxicity; ototoxicity; anaphylaxis; severe skin reactions); ii) serious: requiring discontinuation of therapy (other nephrotoxicity; seizures; pseudomembranous colitis; other allergic reactions); iii) any other (other gastrointestinal; other allergic reactions).
Search methods for identification of studies
We searched the Cochrane Controlled Trials Register, (CENTRAL), (The Cochrane Library, Issue 3, 2004) using the same search terms. We searched the following electronic databases in combination with the search strategy developed by The Cochrane Collaboration and detailed in the Cochrane Handbook for Systematic Reviews of Interventions to limit the search for randomized or quasirandomized trials (Higgins 2005): 1. MEDLINE (1966 to July 2004) using the search: (aminoglycoside* OR netilmicin* OR gentamicin* OR amikacin* OR tobramycin* OR streptomycin* OR isepamicin* OR sisomicin*) AND (combination OR combi*). In a second search, the terms (combination OR combi*) were replaced by endocarditis, Staphylococcus, Streptococcus or pneumonia to enhance the sensitivity and specificity of our search to these infections. 2. EMBASE (1980 to March 2003) using the same search terms. 3. LILACS (1982 to July 2004) using the same search terms. Searching other resources We searched the Interscience Conference of Antimicrobial Agents and Chemotherapy conference proceedings (1995 to 2003) for relevant abstracts. We contacted the first or corresponding author of each included study, and the researchers active in the field, for information regarding unpublished trials or complementary information on their own trials. We also checked the citations of major reviews and of all trials identified by the above methods for additional studies. We did not have a language restriction.
Data collection and analysis Study selection One author (MP) inspected the abstract of each reference identified in the search and applied the inclusion criteria. Where relevant articles were identified, the full article was obtained and inspected independently by two authors (MP, IS or LL).
Electronic searches
Quality assessment
We formulated a comprehensive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). The key words used for the search strategy are shown in Appendix 1. We searched the Cochrane Infectious Diseases Group specialized trials register for relevant trials up to December 2002 using the search terms: ((aminoglycoside* OR netilmicin* OR gentamicin* OR amikacin* OR tobramycin* OR streptomycin* OR isepamicin* OR sisomicin*) AND (pneumonia* OR infection OR infect* OR sepsis OR bacter* OR bacteremia OR septicemia).
We assessed the quality of the trials to be included for allocation sequence, allocation concealment, blinding, fatality outcome reporting, intention-to-treat analysis, and number of patients excluded from outcome assessment. Two authors (MP, IS or KSW) independently performed quality assessment. We based methodological quality classification on the evidence of a strong association between poor allocation concealment and over estimation of effect. We defined it as: A (low risk of bias; adequate allocation concealment); B (moderate risk of bias; some doubt about allocation concealment); and C (high risk of bias; inadequate allocation
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concealment) (Schulz 1995). We performed sensitivity analyses to assess the effect of study quality measures on effect estimates. We intend to assess the effect of number of exclusions on effect estimates (above or below 20%) in future updates of the review. Data collection Two authors (MP, IS or SG) independently extracted data from included trials. In case of disagreement between the two authors, a third author (KSW, LL) independently extracted the data. A third author (KSW or LL) also extracted the data in 10% of the studies, selected at random. We discussed data extraction, documented decisions, and contacted authors of all studies for clarification. We resolved differences in the data extracted by discussion. We also documented the justification for excluding studies from the review. We identified the trials by the name of the first author and the year in which the trial was first published, and listed in chronological order. We extracted, checked and recorded the following data. Characteristics of trials: 1. date, location, and setting of trial; 2. publication status; 3. country of origin; 4. design (intention-to-treat, method of randomization); 5. duration of study follow-up; 6. performance of surveillance cultures (routine cultures for the detection of colonization); 7. sponsor of trial. Characteristics of patients: 1. number of participants in each group; 2. age (mean and standard deviation, or median and range); 3. number of patients with renal failure before treatment; 4. number of patients with shock. Characteristics of infection: 1. number of patients with infections caused by bacteria resistant to the administered beta lactam antibiotic; 2. number of patients with nosocomial infections; 3. number of patients with bacteremia; 4. number of patients with bacteriologically documented infection; 5. number of patients with infections caused by Gramnegative bacteria; 6. number of patients with Gram-negative bacteremia; 7. number of patients with documented Pseudomonas infections (Pseudomonas isolated in the blood or specimen(s) obtained from suspected site(s) of infection); 8. number of patients with: i) urinary tract infection; ii) pneumonia; iii) intra-abdominal infection; iv) skin and soft tissue infection; and v) infection of unknown origin. Characteristics of interventions:
1. antibiotic type and dose; 2. duration of therapy (mean). Characteristics of outcome measures: 1. number of deaths at the end of the follow-up period; 2. number of patients failing treatment (as defined); 3. adverse reactions (as defined) in each group; 4. loss of follow-up (dropouts) before the end of the study in each group; 5. number of patients developing super-infection; 6. number of patients developing colonization (as defined) with resistant bacteria; 7. duration of fever and hospital stay. We collected outcome measures on an intention-to-treat basis whenever possible. Where such data were not presented, we sought information from the authors, and if unavailable, per-protocol results were used. For failure outcome, we performed sensitivity analyses comparing these results with a ’presumed all intention to treat’, which we achieved by counting all dropouts as failures. We could not make such an assumption in studies that did not specify the number of dropouts per study arm, and we analysed these studies separately. Data synthesis We calculated relative risks for dichotomous data. Continuous outcomes were unavailable for this review. We will use weighted mean differences for continuous outcomes in future updates of the review. We initially assessed heterogeneity in the results of the trials using a chi-squared test of heterogeneity (p < 0.1). We used a fixed effect model throughout the review, as the I2 measure of inconsistency was low for all comparisons. We compared results obtained by the fixed effect model to those obtained by a random effect model for the major outcomes. We explored the following factors to explain heterogeneity in relation to the major outcomes: 1. infections caused by Pseudomonas sp. versus all other infections; 2. Gram-negative versus all other infections; and 3. urinary tract infections versus other sites of infection. We performed subgroup analysis by these factors where data were available. For subgroup analyses we extracted all-cause fatality and treatment failures outcomes. We adjusted the descriptive mean mortality rate in included studies to the inverse of the mortality variance between the trials. We examined a funnel plot of SE(log(relative risk)) versus relative risk of each study in order to estimate potential selection bias (publication and language).
RESULTS Description of studies
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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See: Characteristics of included studies; Characteristics of excluded studies. The search strategy resulted in 5568 references. We filtered double references, and screened 2805 different abstracts for inclusion. We did not evaluate studies in which the comparator antibiotic regimens were clearly incompatible with inclusion criteria in depth. We similarly excluded non-randomized and non-human studies. We retrieved 145 studies for full-text inspection, of which we excluded 67 publications, representing 63 studies (see table of ’ Characteristics of excluded studies’), and categorized two as awaiting assessment (see Additional Table 1, and ’Table of studies awaiting assessment’). Several studies compared monotherapy versus combination therapy among patients with cystic fibrosis. Patients in these studies typically do not have fever or other signs of sepsis when entering the trial, and thus did not fulfil inclusion criteria for this review. These studies are included in a separate review ( Elphick 2001). Seventy-eight studies fulfilled inclusion criteria. Fourteen were double publications, and thus we have included 64 trials in this review. We requested complementary information from nearly all the authors, and included complementary data in 22 studies (see references to studies). Table 1. Table of studies awaiting assessment
Study ID
Explanation
Alberto 1999
According to abstract (LILACS) patients with community acquired pneumonia were divided (’al azar’) randomly to ceftazidime versus penicillin + amikacin. Awaiting full text availability for inclusion and data extraction.
Figueroa Damian 1996
According to abstract (LILACS) patients were included sequentially (Aleatoriamente), and given piperacillin-tazobactam or ampicillin + gentamicin for postcaesarean endometiris. Awaiting full text availability to inspect whether study indeed randomized.
We have detailed study characteristics in the table of ’ Characteristics of included studies’. The included studies were performed between the years 1968 to 2001. Twenty-two were multi-centred. Twenty-one were performed in the USA or Canada, 34 in Europe, and 10 in other countries. The studies included 7586 patients. The median number of included patients per trial was 87.5 (range 20 to 580). Two trials ( Cardozo 2001; Naime Libien 1992) included children, while all other trials were restricted to or included mostly adults.
Contact details
The studies differed by the type of population and infection targeted (see table of ’ Characteristics of included studies’). Most trials (designated ’sepsis’) included patients with severe sepsis, suspected Gram-negative infections (25 trials), or pneumonia (16 trials). The adjusted mean fatality rate in these studies was 8.6%. Eleven trials included patients with intra-abdominal infections, related mainly to the biliary tract (designated ’abdominal’). The mean fatality in these trials was 1.7%. Seven trials were restricted to patients with urinary tract infections (UTIs), all hospitalized, mainly women (UTI). Five of these studies reported fatality, and no deaths occurred in four. Finally, five of the studies included in
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the review targeted patients with Gram-positive infections, mainly endocarditis. We will present results for these infections separately, in addition to their inclusion in the overall analysis. Most studies compared the initial, empirical antibiotic treatment administered to the patients. Four studies assessed the empirical treatment of a specific infection by randomizing patients empirically and evaluating only those subsequently fulfilling criteria for the specific infection. Two such studies randomized patients with suspected endocarditis and evaluated only those with Staphylococcus aureus bacteremia and proven endocarditis (Abrams 1979; Korzeniowski 1982). The other two randomized patients with suspected biliary tract infections and evaluated only patients with a surgically proven diagnosis (Gerecht 1989; Yellin 1993). Nonevaluated patients in these studies were not counted as dropouts, since the study design defined evaluation only for patients fulfilling definitive criteria. Eight studies, focusing on patients with specific infections or pathogens (e.g., cholecystitis, Staphylococcal infections, etc.), tested the effect of monotherapy versus combination therapy semi-empirically. In these studies (designated ’semiempirical’, see table of ’ Characteristics of included studies’) randomization occurred after the specific infection was documented, and patients could have received prior antibiotic treatment for this infection. Analysis of empirical and semi-empirical studies was not
separated. The specific antibiotic regimens used are detailed in the table of ’ Charcteristics of included studies’. Forty-four studies compared a single beta-lactam drug to a different, narrower spectrum, beta-lactam combined with an aminoglycoside (designated ’different BL’). Sixteen ’different BL’ studies reported baseline susceptibility rates of the pathogens isolated on admission to the beta-lactam. The beta-lactam used in the combination arm covered less pathogens than the monotherapy beta-lactam in 13 studies, while the opposite occurred in two studies only. Twenty studies compared the same beta-lactam (designated ’same BL’). Results obtained from studies comparing same and different beta-lactams were kept separated throughout all efficacy analyses. The aminoglycoside was administered once daily in six trials (Cardozo 2001; Jaspers 1998; Rubinstein 1995; Sandberg 1997; Sexton 1998; Speich 1998). Other trials administered the aminoglycosides multiple daily (47 trials), or did not specify the administration schedule (11 trials). Mean antibiotic treatment duration ranged between 4 to 17.5 days in the sepsis studies, 6.8 to 11.9 in the abdominal studies, 4.1 to 7 days in the UTI studies, and 2 to 4 weeks in the endocarditis studies.
Risk of bias in included studies (See Additional Table 2: Study quality assessment table.)
Table 2. Study quality assessment Study ID
Alloc. generation
Alloc. concealment Blinding
Intention to treat
Lost to follow up
Abrams 1979
No information
No information
None
No
12 of 36 randomized patients, but none out of patients fulfilling pre-specified inclusion criteria (staphylococcus aureus bacteremia)
Aguilar 1992
No information
No information
None
Unknown
No reference to dropouts in study
Alvarez-Lerma 2001
Computer gen- Central and sealed erated in blocks of 6 opaque envelopes patients
For mortality only
24 of 140 randomized patients for failure
Arich 1987
Table of random Sealed opaque en- None numbers velopes
No
18 of 65 randomized patients
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Table 2. Study quality assessment
(Continued)
Bergeron 1988
No information
No information
None
No
11 of 77 randomized patients
Biglino 1991
No information
No information
None
Unknown
No reference to dropouts in study
Brown 1984
Random table
No information
Single, outcome as- So sessor
14 of 48 randomized patients
Carbon 1987
No information
No information
None
Unknown
No reference to dropouts in study
Cardozo 2001
Numerical assigna- No information tion
None
Unknown
No reference to dropouts in study
Cometta 1994
Table of random Sealed, opaque None numbers numbered envelopes
No
33 of 313 randomized patients
Cone 1985
No information
None
No
17 of 57 randomized patients
Coppens 1983
Consecutively num- Envelopes (sealed or None bered envelopes opaque not mentioned)
No
14 of 80 randomized patients
D’Antonio 1992
Table of random Sealed opaque en- None numbers, stratified velopes. according to underlying malignancy
For mortality only
17 of 300 randomized patients for failure
Duff 1982
Based on the last No information digit of the hospitalization number odds/ evens
None
Yes
None
Dupont 2000
Computer gen- Central erated in blocks of 4 patients
Single, evaluation No committee
14 of 241 randomized patients
Felisart 1985
Table of random No information numbers
None
None
No information
Yes
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Table 2. Study quality assessment
(Continued)
Finer 1992
Computer generated
Sealed, opaque en- None velopes
For mortality only
56 of 471 randomized patients for failure
Gerecht 1989
Computer gen- No information erated table of random numbers
None
No
4 of 50 randomized patients fulfilling operative and bacteriological criteria for cholangitis
Gomez 1990
Computer generated
Sealed, closed en- None velopes
No
119 of 197 randomized patients, but none out of patients fulfilling pre-specified inclusion criteria (gramnegative bacteremia)
Havig
Consecutive accord- No information ing to a randomized list prepared in advance
None
No
22 of 90 randomized patients
Hoepelman 1988
Randomization lists Sealed opaque en- none made by hand velopes
Yes
None
Holloway 1985
No information
None
No
10 of 43 randomized patients
Iakovlev 1998
Parallel groups, us- Envelopes (sealed or None ing the envelope opaque not menmethod tioned)
Yes
None
Jaspers 1998
Table of random Sealed opaque en- None numbers in consec- velopes utive envelopes
Yes
None
Klastersky 1973
No information
None
No
7 of 75 randomized patients
Kljucar 1990
ComClosed envelopes puter generated in consecutively numbered envelopes
None
No
1 of 150 randomized patients
No information
No information
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Table 2. Study quality assessment Koehler 1990
No information
Korzeniowski 1982
(Continued) No information
None
For mortality only
17 of 144 randomized patients for failure
Table of random Central numbers
None
No
82 of 156 randomized patients, but only 4 of 78 patients fulfilling pre-specified inclusion criteria (Staphylococcus aureus endocarditis)
Landau 1990
According to last No information digit of identification number
None
Unknown
No reference to dropouts in study
Limson 1988
No information
None
No
14 of 54 randomized patients
Mandell 1987
Consecutive blocks of four
in Sealed en- None velopes (opaque not mentioned)
No
19 of 129 randomized patients
Martin 1991
Randomization ta- No information ble
None
No
22 of 116 randomized patients
McCormick 1997
Table of random Sealed, opaque en- None numbers velopes
No
19 of 147 randomized patients
Mergoni 1987
No information
Sealed opaque en- None velopes
Unknown
No reference to dropouts in study
Moreno 1997
No information
No information
None
No
12 of 70 randomized patients
Mouton 1990
No information
No information
None
Yes
None
Mouton 1995
No information
No information
None
For mortality only
43 of 272 randomized patients for failure
Muller 1987
Computer generated lists
No information
None
No
25 of 131 randomized patients
No information
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Table 2. Study quality assessment
(Continued)
Naime Libien 1992
No information
No information
None
Unknown
No reference to dropouts in study
Piccart 1984
No information
No information
None
No
20 of 105 randomized patients
Rapp 1984
No information
No information
None
Yes
None
Rasmussen 1986
Table of random numbers
None
No
3 of 62 randomized patients
Ribera 1996
Table of random Sealed, opaque en- None numbers velopes
Yes
None
Rubinstein 1995
Computer generated
Sealed, Single, outcome as- For mortality only opaque, numbered sessors blinded envelopes
75 of 580 randomized patients for failure
Sage 1987
No information
Envelopes
No
13 of 61 randomized patients from arms used in review
Sandberg 1997
ComSealed opaque en- None puter generated lists velopes in blocks of four
For mortality only
22 of 73 randomized patients for failure
Sanfilippo 1989
Computer generated code
Central
Double blind, Unknown placebo controlled
No reference to dropouts in study
Sculier 1982
No information
No information
None
Yes
None
Sexton 1998
No information
No information
None
No
16 of 67 randomized patients
Sieger 1997
No information
No information
None
Yes
None
Smith 1984
Table of random Central numbers
Speich 1998
Computer generated
None
Double blind, No placebo controlled
Sealed opaque en- None velopes.
For mortality only
5 of 200 randomized patients for failure; 13 of 200 randomized patients for mortality 5 of 89 randomized patients for failure
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Table 2. Study quality assessment
(Continued)
Stille 1992
Computer gener- No information ated list of blocks of 16 patients
Sukoh 1994
No information
Takamoto 1994
Yes
None
Envelopes (sealed or None opaque not mentioned).
Unknown
No reference to dropouts in study
Computer generated
Envelopes (sealed or None opaque not mentioned).
No
14 of 171 randomized patients
Thompson 1990
Computer generated
No information
None
No
10 of 106 randomized patients
Thompson 1993
Computer generated
No information
None
No
27 of 147 randomized patients
Trujillo 1992
No information
No information
None
Unknown
No reference to dropouts in study
Vergnon 1985
Tirage a sort
No information
None
Unknown
No reference to dropouts in study
Verzasconi 1995
No information
No information
Single
No
6 of 93 randomized patients
Warren 1983
Random numbers Sealed en- None contained within velopes (opaque not consecutively num- mentioned). bered envelopes
No
3 of 123 randomized patients
Wiecek 1986
No information
Unknown
No reference to dropouts in study
Wing 1998
ComSealed opaque en- None puter generated ran- velopes. dom number table
Yes
None
Yellin 1993
2:1 (mono.: Central combi.), through table of random numbers
no
59 of 149 randomized patients, but only 22 of 112 patients fulfilling pre-specified inclusion crite-
No information
None
None
Single, provider
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Table 2. Study quality assessment
(Continued) ria (infection proven at surgery)
Follow-up Allocation concealment and generation Thirty-three percent of the studies (21/64) reported adequate allocation concealment. Two studies were graded as C (Duff 1982; Landau 1990). No information was available for the other studies (34 studies), or envelopes were used but not described as sealed or opaque (7 studies). Allocation generation was described as adequate in 53% of the studies (34/64). No information was available for 28 studies. Two studies were quasi-randomized, using patient identification numbers (Duff 1982; Landau 1990). Both allocation generation and concealment were considered adequate in 30% of the studies (19/64). Blinding Most studies were open. Two studies, including 226 patients, were double blinded (Sanfilippo 1989; Smith 1984). Outcome assessors were blinded in four studies (Brown 1984; Dupont 2000; Rubinstein 1995; Verzasconi 1995). Clinicians were blinded to the treatment in one study (Yellin 1993). Intention-to-treat versus per-protocol analysis We separated included studies into four different study types with relation to outcome reporting: 1. full Intention-to-treat analysis; 2. per-protocol analysis, in which the number of dropouts was given per study arm; 3. per-protocol analysis, in which the number of dropouts was known, but not given per study arm; 4. studies which did not distinguish between the number of randomized and number of evaluated patients. These studies did not refer to dropouts, yet did not define the study explicitly as intention-to-treat. The distribution of included studies by study type was as follows: All cause fatality (reported in 43 studies): Type 1: 19 studies (44%); Type 2 and 3: 18 studies (42%). As authors cannot make assumptions can be made regarding dropouts for mortality, we have joined study groups 2 and 3 are joined for mortality; Type 4: 6 studies (14%). Treatment failure: (reported In 63 studies); Type 1: 13 studies (21%); Type 2: 23 studies (37%); Type 3: 16 studies (25%); Type 4: 11 studies (17%).
Forty-three studies (67%) specified follow-up duration, while only 18 studies defined a specific time for outcome collection (28%). Follow-up ranged from 48 hours following treatment cessation to 6 months. Outcomes were extracted preferentially at up to 30 days, with the exception of the Gram-positive infection studies, in which the type of infection mandated a longer follow-up (3 to 6 months).
Effects of interventions All cause fatality (see Analysis 1) Forty-three trials including 5527 patients were included in this comparison (see Analysis 1.1). Twelve studies, including 1381 patients, compared the same beta-lactam. These studies showed near equivalence, RR 1.01 (95%CI 0.75-1.35), while studies comparing different beta-lactams tended non-significantly in favour of monotherapy, RR 0.85 (95%CI 0.71-1.01). Analysis was further broken down according to the main study population, excluding Gram-positive infection studies (see Analysis 1.2). The advantage to the monotherapy among studies comparing different beta-lactams was statistically significant in studies addressing ’sepsis’, RR 0.83 (95% CI 0.69-0.99). No heterogeneity was present for these comparisons (I2 = 0% for the same beta-lactam comparison, I2 = 19.4 for different beta-lactams). Subgroup analyses No significant difference between monotherapy and combination therapy was apparent when analysis was restricted to patients with any Gram-negative infection (eight studies) or Gram-negative bacteremia (four studies, see Analysis 1.3 to Analysis 1.4). Only three studies permitted mortality outcome extraction among patients with Pseudomonas aeruginosa infections, and these did not show a differences, either alone or when combined (graph not shown). Five UTI studies reported mortality, and mortality was null in three studies. Excluding patients with urinary tract infection from the analysis (’non-UTI’ subgroup, see Analysis 1.5) strengthened the advantage to monotherapy in studies comparing different betalactams (RR 0.70, 95%CI 0.52-0.95). Sensitivity analyses Adequate allocation concealment and generation were associated with relative risk closer to one, both for studies comparing the
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same and different beta-lactams. (See Analysis 7.1 and Analysis 7.2). Combination therapy was significantly better among studies comparing different beta-lactams classified as B. Blinding was performed in too few studies to assess its effect on mortality. The combined RR for studies comparing the same beta-lactam reporting fatality by intention-to-treat was 0.62 (95% CI 0.27-1.43), compared to 1.09 (95% CI 0.80-1.51) for studies reporting fatality per-protocol (Analysis 7.3). Comparing intention to treat to per-protocol studies for different beta-lactams did not reveal a difference. Re-analysis of the mortality comparison by the random effect model was very similar (RR 1.02, 95% CI 0.76-1.38 for same beta-lactam, RR 0.85 95% CI 0.69-1.05 for different betalactam). Treatment failure (see Analysis 2) We included all trials but one (Wiecek 1986) in the clinical failure analysis, comprising 6616 patients (see Analysis 2.1). We found a significant advantage to monotherapy among studies comparing different beta-lactams, RR 0.77 (95% CI 0.69-0.86). We detected no difference between monotherapy and combination therapy among studies comparing the same beta-lactam, RR 1.11 (95% CI 0.95-1.29). No heterogeneity was present (I2 =0% for both comparisons). Grouping studies according to study population highlighted an advantage to combination therapy among the ’sepsis’ studies that compared the same beta-lactam, RR 1.25 (95%CI 1.01-1.55). This group of studies also accentuated the opposing advantage to monotherapy among studies comparing different beta-lactams (see Analysis 2.2). Bacteriological cure occurred more frequently with monotherapy among studies comparing different beta-lactams, RR 0.81 (95% CI 0.69-0.94), but did not differ significantly in studies comparing the same beta-lactam (see Analysis 2.3). Assessment of efficacy for urinary tract infections included reinfections and relapse as outcomes (see Analysis 2.4). We noted no significant difference between monotherapy and combination therapy , with six trials and 458 patients included in this comparison. Subgroup analyses We analysed 28 studies including 1835 patients with Gram-negative infections and 18 studies including 426 patients with Pseudomonas aeruginosa infections were analysed (see Analysis 2.5 and Analysis 2.7). We observed no significant differences between the study groups, either for studies comparing the same or different beta-lactams. For studies comparing the same beta-lactam the RR was 1.23 (95% CI 0.90-1.68) for Gram-negative infections and 1.02 (95% CI 0.68-1.51) for Pseudomonas aeruginosa infections.
We observed no difference between study groups among patients with Gram-negative bacteremia or any bacteremia (see Analysis 2.6 and Analysis 2.8). The latter comparison mainly comprised of patients with Gram-negative bacteremias but was available from a larger number of studies, and showed an advantage to combination therapy among studies comparing different beta-lactams. Both the subgroups of patients with urinary tract infections (see Analysis 2.8), and patients without urinary tract infections maintained the trends seen previously (Analysis 2.9). Sensitivity analyses The quality of allocation concealment and generation did not affect the relative risks for treatment failure, either among studies comparing the same or different beta-lactams. The two studies graded as C compared different beta-lactams, and were non-significantly closer to one than the truly randomized studies (see Analysis 7.4 to Analysis 7.5). Several studies comparing different beta-lactams used some type of blinding. The advantage to monotherapy was non-significantly larger among these studies, compared to non-blinded studies (see Analysis 7.6). Among studies comparing the same beta-lactam, we observed an advantage to combination therapy in the presumed intention to treat group (type 2 studies), in which we imputed failure for dropouts. Among studies comparing different beta-lactams, intention to treat, presumed intention to treat, and per-protocol results were similar, favouring monotherapy (see Analysis 7.7). Analysis by the random effect model did not change results (RR 1.09, 95% CI 0.94-1.27 for same beta lactams, RR 0.76, 95% CI 0.68-0.97, for different beta-lactams). Length of hospital stay Only four studies contained usable information for the comparison of hospital stay. Significant heterogeneity precluded their combination. Duration of hospitalization was longer with monotherapy in one study (McCormick 1997, 128 patients), shorter in another (Arich 1987, 47 patients), and similar in two (Wing 1998; Yellin 1993, 269 patients). Summary of gain Among studies comparing the same beta-lactam there was no benefit to the combination arm for all mortality comparisons, including subgroup and sensitivity analyses. Treatment failure tended to favour the combination arm reaching statistical significance only among studies addressing ’sepsis’ and when an intention to treat analysis was imposed on studies performed per-protocol, imputing failure for dropouts. Studies using different beta-lactam usually compared a broad-spectrum beta-lactam to a narrower spectrum beta-lactam combined with an aminoglycoside. The mortality comparisons favoured monotherapy reaching statistical significance in several subgroups.
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Treatment failure was significantly in favour of monotherapy overall, among the ’sepsis’ studies, the non-UTI subgroup and in all the methodology sensitivity analyses. No comparison favoured the combination arm. Resistance development and adverse events (see ’Analysis’ 3 and 4) We compared studies comparing same and different beta-lactams for the assessment of resistance development and adverse events. These outcomes are intended to assess the antibiotic class effect of aminoglycoside-beta-lactam combinations versus beta-lactams alone, whether same or different. We detected no significant differences between the rates of bacterial or fungal superinfections (see Analysis 3.1 to Analysis 3.4). Bacterial superinfections occurred more frequently with combination therapy, RR 0.76 (95% CI 0.57-1.01). This was the largest comparison, including 27 studies and 3085 patients. In outcome 5 we compared bacterial colonization rates only in patients from whom surveillance cultures were taken (7 studies, 751 patients). Colonization was, again, non-significantly more frequent with combination therapy, RR 0.78 (95% CI 0.60-1.01). Few studies monitored development of resistance among pathogens isolated initially (Analysis 3.6). We observed no difference between monotherapy and combination therapy. Any adverse event occurred non-significantly more frequently with combination therapy, RR 0.92 (95% CI 0.83-1.01; see Analysis 4.1). We found nephrotoxicity to be more common in the combination arm in nearly all studies, with a highly significant combined
relative risk in favour of monotherapy, RR 0.30 (95% CI 0.230.39, Analysis 4.3). A significantly increased rate of nephrotoxicity was seen both in studies administering the aminoglycoside once daily and in those with a multiple-day regimen. Vestibular and ototoxicity, other known serious side effects of aminoglycoside treatment, were not reported routinely and could not be analysed. Different definitions and detailing of specific adverse events precluded a meaningful meta-analysis of other adverse events, individually or grouped. Dropouts and selection bias (see ’Analysis’ 5) The number of patients excluded from each study arm was nearly equal, both for mortality (RR 1.00, 95% CI 0.66-1.49, Analysis 5.1), and failure (RR 1.04, 95% CI 0.88-1.23, Analysis 5.2) outcomes assessment. This comparison included studies in which these outcomes could only be collected per-protocol, and reported the number of dropouts per study arm. It should be noted that counting dropouts as failures did affect the combined failure results (failure sensitivity analysis above). This is because among studies comparing the same beta-lactam, a slightly higher rate of dropouts occurred in the monotherapy arm, while the opposite occurred among studies comparing different beta-lactams. The funnel plot for treatment failure generated a nearly symmetric ’funnel distribution’ (Figure 1). Funnel plot analysis for all-cause fatality showed that small studies favouring combination therapy may be missing (Figure 2). Mortality outcome was unavailable from 33% of the trials.
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Figure 1. Funnel failure.
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Figure 2. Funnel mortality.All cause mortality
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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ment, and death. Gram positive-infections (see ’Analysis’ 6) Five studies assessed Gram-positive infections specifically. Four studies addressed patients with endocarditis caused by Staphylococcus aureus (Abrams 1979; Korzeniowski 1982; Ribera 1996), or streptococci (Sexton 1998). One study included any staphylococcal infection (Coppens 1983). All of these compared the same betalactam, with or without an aminoglycoside. Although small, we chose to separate this subset of studies and present its meta-analysis, since the rationale and clinical practice of adding an aminoglycoside to the beta-lactam in these infections differ from those underlying combination use in other infections. The comparison included four outcomes: all cause fatality (three studies, outcome 1), clinical and bacteriological failure (five studies, outcomes 2 to 3), and the need for surgery (four endocarditis studies, outcome 4). None of these comparisons showed an advantage to combination therapy. The combined relative risk consistently favoured monotherapy, although differences were nonsignificant. The combined relative risk for clinical failure was 0.69 (95% CI 0.40-1.19, 5 studies, 305 patients). Clinical failure in these studies could be and indeed was defined more rigorously than in other studies. The time of outcome determination was pre-defined in all the trials and the follow-up was longer (1 to 6 months). Measures of treatment failure included persistence of bacteremia or signs of endocarditis, relapse, need for valve replace-
DISCUSSION This present review compares beta-lactam-aminoglycoside antibiotic combinations to beta-lactam monotherapy. The primary outcome we assessed was all-cause fatality. Most studies compared one beta-lactam to a different, narrower spectrum beta-lactam, combined with an aminoglycoside. Twenty of the 64 included studies used the same beta-lactam in both study arms. A special emphasis should be placed on studies comparing the same beta-lactam. These are the studies directly testing the hypothesis that the addition of an aminoglycoside to the beta-lactam is beneficial. Among these studies, all-cause fatality did not differ between study arms (RR 1.02, 95% CI 0.76-1.38). Treatment failure occurred more frequently in the monotherapy arm, reaching statistical significance only in subgroup analyses. In studies comparing different beta-lactams, both failure and mortality were more common in the combination treatment arm. Failure was highly significant, while mortality reached significance only with subgroup analyses. These studies demonstrate an advantage to broad-spectrum beta-lactam monotherapy when compared to a narrower spectrum beta-lactam combined with an aminoglycoside, despite an equal in-vitro coverage of the culprit pathogens in both arms.
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Development of resistance was assessed by the occurrence of superinfections and colonization, assuming that bacteria appearing under antibiotic treatment are resistant to the antibiotic administered. No difference between monotherapy and combination therapy was detected. Adverse events occurred more frequently with combination therapy. Specifically, nephrotoxicity occurred significantly more frequently in the combination treatment arm (RR 0.30, 95% CI 0.23-0.39). We defined all-cause fatality as the primary outcome, while most studies assessed and reported treatment failure as a main outcome. Obviously, the most significant outcome for the patient is survival following the infectious episode. Available evidence shows that the addition of an aminoglycoside to a beta-lactam does not reduce mortality. Replacing beta-lactam monotherapy with a narrower spectrum beta-lactam combined with an aminoglycoside may be associated with increased mortality. Failure was commonly defined as lack of clinical improvement, deterioration, relapse, and/or modifications to the antibiotic treatment. These endpoints are highly subjective and do not necessarily translate to detriments experienced by the patient. Detection bias is a concern in open trials that compared the same beta-lactam, or in trials comparing a ’new’ broad spectrum monotherapy to a conventional antibiotic regimen. Thus, the advantage to monotherapy therapy in studies comparing different beta-lactams, and the opposing advantage to combination therapy in studies comparing the same beta-lactams, may be largely biased. The major adverse event associated with combination therapy was nephrotoxicity. We did not observe a protective effect of the combination with regard to resistance development. During the last decade, once daily administration of aminoglycosides has entered into use, with similar efficacy but lower nephrotoxicity (Barza 1996). Most studies in our review used multiple-day administration schedules for the complete duration of antibiotic therapy or until modification. The RR of 0.30 for any nephrotoxicity we observed may, therefore, be an overestimation. However, the RR among the few studies that did administer the aminglycoside once daily was also highly significant in favour of monotherapy (0.17, 0.06-0.53). The rationale for administering combination therapy arose from in-vitro studies showing synergistic bactericidal activity of specific beta-lactam-aminoglycoside antibiotic combinations. Synergy has been observed for Pseudomonas aeruginosa (Giamarellou 1984), other Gram-negative bacteria (Giamarellou 1986; Klastersky 1976), and Staphylococci (Sande 1975; Sande 1976). Assessment of antibiotic efficacy against specific infections in randomized trials must either be limited to definitive treatment (randomisation performed when infection is microbiologically documented), or be performed as a subgroup analysis to assess empirical treatment (randomizing patients empirically and assessing those with documented infections). Eight studies assessed definitive treatment
(semi-empirical studies), while most assessed empirical treatment. We did not find an advantage to combination therapy among patients with any Gram-negative infection, Gram-negative bacteremia, or Pseudomonas aeruginosa infections. Lack of data precluded the assessment of Pseudomonas aeruginosa bacteremia. In a previous non-randomized prospective study of bacteremic patients, we showed that appropriate beta-lactam monotherapy was as effective as appropriate beta-lactam aminoglycoside combination therapy, both empirically and semi-empirically. Appropriate single aminoglycoside monotherapy was associated with increased mortality (Leibovici 1997). Combination therapy was claimed superior to monotherapy in a prospective observational study of patients with Pseudomonas aeruginosa bacteremia, but most patients in the monotherapy group received aminoglycosides (Hilf 1989). In a meta-analysis including non-randomized trials (mostly retrospective cohort studies), Safdar and colleagues found a reduction in mortality with combination therapy for patients with Pseudomonas aeruginosa bacteremia (5 studies; OR 0.50, 95%CI 0.32-0.79), but not for patients with Gram-negative bacteremia (17 studies; OR 0.96, 95% CI 0.79-1.32). Monotherapy, however, included single aminoglycoside treatment, and analysis was not performed separately for beta-lactam monotherapy (Safdar 2004). Finally, in a previous systematic review and meta-analysis of randomized trials comparing combination therapy to beta-lactam monotherapy for febrile neutropenic patients, no advantage was seen for the combination (Paul 2001). Overall, empirical evidence does not show the synergy effect when adding an aminoglycoside to a betalactam in the clinical setting. Why does synergy, observed in-vitro, not translate into clinical benefit? Specific growth conditions invitro, unattainable in-vivo, may induce synergism. Pharmacokinetic and pharmacodynamic properties involving specific antibiotics, sites of infection, timing and intervals of administration may prevent synergism in-vivo. Adverse events related directly to the aminoglycoside, or to the combination, may interfere with an invivo benefit, amounting altogether to no benefit. A small subset of studies in our review addressed patients with Gram-positive infections, mainly Staphylococcus aureus endocarditis. No study assessed enterococcal infections specifically. In these, also, no outcome was improved by the addition of an aminoglycoside. Current guidelines for the treatment of Staphylococcus aureus endocarditis advise the addition of an aminoglycoside to the betalactam, at least initially (Bayer 1998). These recommendations rely mainly on in-vitro data (Sande 1975; Sande 1976). Animal studies have shown that sterilization of cardiac vegetations may be achieved more rapidly with combination therapy (Sande 1975; Sande 1976). One clinical study included in our review showed that combination therapy shortened the duration of bacteremia, but this comparison was performed according to the empirical antibiotic regimen, while randomization occurred either empirically or semi-empirically (Korzeniowski 1982). We could not show an advantage to combination therapy combining all trials in humans.
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On the contrary, all outcomes tended to favour monotherapy, although statistical significance was not reached. The limitations of our analysis may originate from the quality of data reported in available studies and from our analysis of these data. Of these, we emphasize the lack of data for all-cause fatality from a third of included studies. Survival, with or without the more subjective assessment of infection-related mortality, must be reported comparatively in all trials. Data for subgroups most likely to benefit from combination therapy were also not available from all studies. In our analysis, we did not correct for the appropriateness of antibiotic treatment, which has been shown conclusively to correlate with survival (Ibrahim 2000; Leibovici 1998). Data were not fully available to perform such an analysis. However, among studies comparing the same beta-lactam, combination therapy by definition broadened the spectrum of coverage, without improving outcomes. In studies comparing different beta-lactams, inappropriate beta-lactam was used more frequently in the combination arm, which may partially explain the advantage to monotherapy. We conclude that the addition of an aminoglycoside to a beta-lactam does not improve the clinical efficacy achieved with the betalactam alone. Substituting a narrow-spectrum beta-lactam with an aminoglycoside for a single broad-spectrum beta-lactam, will result in increased failure rates and may be associated with increased mortality. Adverse events occur more frequently with combination treatment. Short-term combination therapy for sepsis does not prevent development of resistant bacteria, as assessed by superinfection or colonization rates following antibiotic treatment. Thus, the use of beta-lactam-aminoglycoside combination therapy for sepsis should be discouraged.
AUTHORS’ CONCLUSIONS Implications for practice Clinicians usually face the dilemma of selecting an antibiotic treatment on two occasions during an un-complicated infectious episode. On the initial encounter with a patient the clinician must prescribe empirical antibiotic treatment, since the causative pathogen and its susceptibilities are generally unknown. Most studies addressed this situation, and the results show that there is no difference in overall mortality whether monotherapy or combination therapy is used. Adverse effects, most significantly nephrotoxicity, will occur more frequently with combination therapy. If the choice is between a narrower-spectrum beta-lactam combined with an aminoglycoside versus a broad-spectrum beta-lactam, our results show that treatment will ultimately have to be modified more frequently if the combination is chosen. We have not identified a specific site of infection, or disease severity, where combination treatment has an advantage.
The second decision point occurs when the causative pathogen is identified. Here, the choice of the antibiotic treatment is dictated by known susceptibility results. However, the question remains, whether for specific bacteria beta-lactam-aminoglycoside combination treatment offers an advantage over single beta-lactam treatment. We addressed this question by subgroup analyses of patients with documented infections caused by specific pathogens (Gramnegatives, Pseudomonas aeruginosa, Staphylococcus aureus). In addition, several semi-empirical studies addressed this question specifically. We have not identified a specific pathogen, or pathogen group, where combination therapy is advantageous. Overall, appropriate beta-lactam monotherapy should be used. Beta-lactam-aminoglycoside combination therapy does not offer an advantage, and is associated with an increased rate of adverse events.
Implications for research We cannot point to a specific patient subgroup that showed a trend for benefit with combination therapy. The design of existing studies did not permit a comparison between monotherapy and combination therapy for specific pathogens when all the antibiotics administered matched the in-vitro susceptibility of the pathogen. However the large body of studies that were performed did not point towards any benefit. Thus we do not see the justification for such future trials. Exceptions to this are trials addressing patients with endocarditis. Prolonged combination treatment for endocarditis, including an aminoglycoside, is well accepted in clinical practice, but does not seem grounded in clinical evidence. Future trials must examine the justification for this practice. Further comparisons between monotherapy and combination, if performed, should be limited to comparisons involving the same beta-lactam. This is the only design that explores the benefit of beta-lactam-aminoglycoside combination therapy. Studies comparing broad-spectrum monotherapy, such as new antibiotics, to an older generation beta-lactam with an aminoglycoside should not be performed. Patients may be harmed by combination therapy in such trials. Appropriate antibiotic treatment has been shown to significantly reduce mortality, and should therefore be reported with results adjusted to it. Outcomes relevant to patients, such as survival and hospitalisation duration should be assessed. Survival, if not assessed as a primary outcome, must at least be reported.
ACKNOWLEDGEMENTS We would like to thank all the authors who responded to our requests for additional data (see ’unpublished data’ and ’unpublished data sought but not used’, ’References to studies’). Dr Solomkin
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(Solomkin 1986) and Dr. Sexton (Sexton 1984) supplied supplementary data for their studies, which were not included in the review. Dr. Finer and Dr. Goustas of the GlaxoSmithKline Company supplied detailed data for their study (Finer 1992). Dr Kora Huber sent completed trial results for Kljucar 1990 and supplied requested additional information. Ms Mary Forrest (Managing editor, Journal of Chemotherapy), sent several publications that were not available to us. We would also like to warmly thank Ms Rika Fujiya who translated the Japanese studies (Sukoh 1994; Takamoto 1994). We thank Dr Vittoria Lutje, Dr Harriet G. MacLehose, and Ms Rieve Robb (Review Group Co-ordinator) of the Cochrane Infectious Diseases Group. We thank Dr Harald Herkner, Prof. Nathan Pace, Kathie Godfrey, Janet Wale and Jane Cracknell (Review Group Co-ordinator) of the Cochrane Anaesthesia Review Group. Both groups supported and provided helpful revisions for this review. This review was initially developed within the Infectious Diseases Group and supported by a grant from the Department for International Development, UK. The review was transferred to the Anaesthesia Group in May 2005.
REFERENCES
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Bergeron 1988 {published data only} Bergeron MG, Mendelson J, Harding GK, Mandell L, Fong IW, Rachlis A, et al.Cefoperazone compared with ampicillin plus tobramycin for severe biliary tract infections. 13th International Congress of Chemotherapy. 1983. ∗ Bergeron MG, Mendelson J, Harding GK, Mandell L, Fong IW, Rachlis A, et al.Cefoperazone compared with ampicillin plus tobramycin for severe biliary tract infections. Antimicrobials Agents and Chemotherapy 1988;32(8):1231–6. Biglino 1991 {published data only} Biglino A, Bonasso M, Gioannini P. Imipenem/cilastatin as empirical treatment of severe infections in compromised patients. Journal of Chemotherapy 1991;3 Suppl 1:208–12. Brown 1984 {published data only} Brown RB, Lemeshow S, Teres D. Moxalactam vs carbenicillin plus tobramycin: Treatment of nosocomial gram-negative bacillary pneumonias in non-neutropenic patients. Current therapeutic research, clinical and experimental 1984;36(3):557–64. Carbon 1987 {published data only} Carbon C, Auboyer C, Becq Giraudon B, Bertrand P, Gallais H, Mouton Y, et al.Cefotaxime (C) vs cefotaxime + amikacin (C + A) in the treatment of septicemia due to enterobacteria: a multicenter study. Chemioterapia 1987;6(2 Suppl):367–8. Cardozo 2001 {published and unpublished data} Cardozo M, Basualdo W, Martinez R, Matsumura K, GonzalezCabello M, Navarro D, et al.Evolution of the association amoxicillin/sulbactam to a amoxicillin/sulbactam more gentamicins in chil-
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dren with peritonitis of apendicular origin [Evaluacion de la asociacion amoxicilina/sulbactam frente a amoxicilina/sulbactam mas gentamicina en ninos con peritonitis de origen apendicular]. Pediatr. (Asuncion) 2001;28(2):15–19.
Finer 1992 {published and unpublished data} Finer N, Goustas P. Ceftazidime versus aminoglycoside and (ureido)penicillin combination in the empirical treatment of serious infection. Journal of the Royal Society of Medicine 1992;85(9):530–3.
Cometta 1994 {published and unpublished data} ∗ Cometta A, Baumgartner JD, Lew D, Zimmerli W, Pittet D, Chopart P, et al.Prospective randomized comparison of imipenem monotherapy with imipenem plus netilmicin for treatment of severe infections in nonneutropenic patients. Antimicrobial Agents and Chemotherapy 1994;38(6):1309–13. Iten A, Cometta A, Eggimann P, Siegrist H, Francioli P. The addition of netilmicin (NET) to imipenem (IMIP) does not prevent the emergence of bacteria resistant (R) to IMIP during treatment (ttt) of severe infections. 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy. 1992; Vol. Abstract no. 522:198.
Gerecht 1989 {published data only} Gerecht WB, Henry NK, Hoffman WW, Muller SM, LaRusso NF, Rosenblatt JE, et al.Prospective randomized comparison of mezlocillin therapy alone with combined ampicillin and gentamicin therapy for patients with cholangitis. Archives of Internal Medicine 1989;149(6):1279–84.
Cone 1985 {published data only} Cone LA, Woodard DR, Stoltzman DS, Byrd RG. Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia. 23rd Interscience Conference Antimicrobial Agents and Chemotherapy. 1983; Vol. Abstract no. 843. ∗ Cone LA, Woodard DR, Stoltzman DS, Byrd RG. Ceftazidime versus tobramycin-ticarcillin in the treatment of pneumonia and bacteremia. Antimicrobial Agents and Chemotherapy 1985;28(1):33–6. Coppens 1983 {published data only} Coppens L, Hanson B, Klastersky J. Therapy of staphylococcal infections with cefamandole or vancomycin alone or with a combination of cefamandole and tobramycin. Antimicrobial Agents and Chemotherapy 1983;23(1):36–41. D’Antonio 1992 {published and unpublished data} D’Antonio D, Fioritoni G, Iacone A, Dell’Isola M, Natale D, D’Arcangelo L, et al.Randomized comparison of ceftriaxone versus ceftriaxone plus amikacin for the empirical treatment of infections in patients with altered host defense: microbiological and clinical evaluation. Chemotherapy 1992;38(6):420–7. Duff 1982 {published and unpublished data} Duff P, Keiser JF. A comparative study of two antibiotic regimens for the treatment of operative site infections. American Journal of Obstetrics and Gynecology 1982;142(8):996–1003. Dupont 2000 {published data only} Dupont H, Carbon C, Carlet J, and the Severe Generalized Peritonitis Study Group. Monotherapy with a broad-spectrum beta-lactam is as effective as its combination with an aminoglycoside in treatment of severe generalized peritonitis: a multicenter randomized controlled trial. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1998; Vol. Abstract MN–48:602. ∗ Dupont H, Carbon C, Carlet J, for The Severe Generalized Peritonitis Study Group. Monotherapy with a broad-spectrum betalactam is as effective as its combination with an aminoglycoside in treatment of severe generalized peritonitis: a multicenter randomized controlled trial. Antimicrobial Agents and Chemotherapy 2000;44(8): 2028–33. Felisart 1985 {published data only} Felisart J, Rimola A, Arroyo V, Perez-Ayuso RM, Quintero E, Gines P, et al.Cefotaxime is more effective than is ampicillin-tobramycin in cirrhotics with severe infections. Hepatology 1985;5(3):457–62.
Gomez 1990a {published and unpublished data} Gomez J, Moldenauer F, Ruiz G, Canteras M, Redondo C, Molina B, et al.[Monotherapy (ceftazidime) versus combination therapy (cefradine + amikacin) in gram-negative bacteremia. A prospective, randomized study, 1987] In Spanish. Revista Espanola de Quimioterapia 1990;3(1):35–40. Havig 1973 {published data only} Havig O, Hertzberg J. [Effect of ampicillin, chloramphenicol and penicillin + streptomycin in the treatment of acute cholecystitis]. Tidsskrift for den Norske laegeforening 1975;95(5):298–300. ∗ Havig O, Hertzberg J. Effect of ampicillin, chloramphenicol, and penicillin-streptomycin in acute cholecystitis. Scandinavian Journal of Gastroenterology 1973;8(1):55–8. Hoepelman 1988 {published and unpublished data} Hoepelman IM, Rozenberg-Arska M, Verhoef J. Comparative study of ceftriaxone monotherapy versus a combination regimen of cefuroxime plus gentamicin for treatment of serious bacterial infections: the efficacy, safety and effect on fecal flora. Chemotherapy 1988;34(Suppl 1):21–9. Hoepelman IM, Rozenberg-Arska M, Verhoef J. Comparison of once daily ceftriaxone with gentamicin plus cefuroxime for treatment of serious bacterial infections. 27th Interscience Conference on Antimicrobials Agents and Chemotherapy. 1987; Vol. Abstract no. 89. ∗ Hoepelman IM, Rozenberg-Arska M, Verhoef J. Comparison of once daily ceftriaxone with gentamicin plus cefuroxime for treatment of serious bacterial infections. Lancet 1988;1(8598):1305–9. Holloway 1985 {published data only (unpublished sought but not used)} Holloway WJ. Treatment of infections in hospitalized patients with ticarcillin plus clavulanic acid. A comparative study. American journal of Medicine 1985;79(5B):168–71. Iakovlev 1998 {published data only} Iakovlev SV, Iakovlev VP, Derevianko, II, Kira EF, and the Meropenem Study Group. [Multicenter open randomized trial of meropenem in comparison to ceftazidime and amikacin used in combination in severe hospital infections]. In Russian. Antibiotiki i Khimioterapiia 1998;43(1):15–23. Jaspers 1998 {published and unpublished data} Jaspers CA, Kieft H, Speelberg B, Buiting A, van Marwijk Kooij M, Ruys GJ, et al.Meropenem versus cefuroxime plus gentamicin for treatment of serious infections in elderly patients. Antimicrobial Agents and Chemotherapy 1998;42(5):1233–8. Klastersky 1973 {published data only} Klastersky J, Cappel R, Daneau D. Therapy with carbenicillin and gentamicin for patients with cancer and severe infections caused by gram-negative rods. Cancer 1973;31(2):331–6.
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Kljucar 1990 {published and unpublished data} ∗ Kljucar S, Heimesaat M, von Pritzbuer E, Bauernfeind A. Comparative clinical trial with ceftazidime (CAZ) versus ceftazidime plus tobramycin (TOB) versus azlocillin (AZL) plus tobramycin in ventilated patients with nosocomial lower respiratory tract infections (LRTI). 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1990:Abtract no. 953. Kljucar S, Heimesaat M, von Pritzbuer E, Olms K. [Ceftazidime with and without tobramycin versus azlocillin plus tobramycin in the therapy of bronchopulmonary infections in intensive care patients]. In German. Infection 1987;15(Suppl 4):S185–S191. Koehler 1990 {published data only} Koehler CO, Arnold H. Controlled clinical study of ceftazidime (3 x 1 g daily) versus piperacillin + tobramycin in patients with nosocomial pneumonia. International Journal of Experimental and Clinical Chemotherapy 1990;3(4):211–8. Korzeniowski 1982 {published data only} Korzeniowski O, Sande MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: A prospective study. Annals of Internal Medicine 1982;97(4):496–503. Landau 1990 {published data only} Landau Z, Feld S, Krupsky M. [Ceftriaxone or combined cefazolingentamicin for complicated urinary tract infections]. In Hebrew. Harefuah 1990;118(3):152–3. Limson 1988 {published data only (unpublished sought but not used)} Limson BM, Navarro Almario E, Litam P, Que E, Kua LT. Ceftazidime monotherapy compared with amikacin/ticarcillin combination therapy in severe infections. Journal of the Philippines Medical Association 1988;64(1):33–5. ∗ Limson BM, Navarro Almario E, Litam P, Que E, Kua LT. Ceftazidime versus a combination of amikacin and ticarcillin in the treatment of severe infections. Clinical Therapeutics 1988;10(5):589–93. Mandell 1987 {published data only (unpublished sought but not used)} Mandell LA, Nicolle LE, Ronald AR, Duperval R, Robson HG, Feld R, et al.A multicentre prospective randomized trial comparing ceftazidime with cefazolin/tobramycin in the treatment of hospitalized patients with non- pneumococcal pneumonia. Journal of Antimicrobial Chemotherapy 1983;12(Suppl A):9–20. ∗ Mandell LA, Nicolle LE, Ronald AR, Landis SJ, Duperval R, Harding GK, et al.A prospective randomized trial of ceftazidime versus cefazolin/tobramycin in the treatment of hospitalized patients with pneumonia. Journal of Antimicrobial Chemotherapy 1987;20(1):95– 107. Martin 1991 {published data only} Martin PY, Unger PF, Auckenthaler R, Waldvogel FA. Efficacy and costs of treatment with ceftriaxone compared to ampicillin-gentamycin in acute pyelonephritis. In French [Efficacite et cout d’un traitement de ceftriaxone compare a l’ampicilline–gentamicine dans les pyelonehrites aigues]. Reveu Medicale Suisse Romande 1991;111 (7):609–17. McCormick 1997 {published and unpublished data} McCormick PA, Greenslade L, Kibbler CC, Chin JK, Burroughs AK, McIntyre N. A prospective randomized trial of ceftazidime versus netilmicin plus mezlocillin in the empirical therapy of presumed sepsis in cirrhotic patients. Hepatology 1997;25(4):833–6.
Mergoni 1987 {published and unpublished data} Mergoni M, Stocchetti N, De Cristofaro A, Antonioni M, Zuccoli P. Azlocillin versus azlocillin plus amikacin in the treatment of severe infections in intensive care unit patients. Chemioterapia 1987;6(4): 286–9. Moreno 1997 {published data only} Moreno A, Vilardell J, Ricart MJ, Claramonte X, Campistol JM, Oppenheimer F. Efficacy of several empirical antibacterial treatment regimens in renal transplant patients with fever [Eficacia de varias pautas de tratamiento empirico antibacteriano en pacientes receptores de trasplante renal con fiebre]. Revista Espanola De Quimioterapia 1997;10(2):138–45. Mouton 1990 {published data only} Mouton Y, Deboscker Y, Bazin C, Fourrier F, Moulront S, Philippon A, et al.[Prospective, randomized, controlled study of imipenemcilastatin versus cefotaxime-amikacin in the treatment of lower respiratory tract infection and septicemia at intensive care units], in French. Presse Medicale 1990;19(13):607–12. Mouton 1995 {published data only} Mouton YJ, Beuscart C, and the Meropenem Study Group. Empirical monotherapy with meropenem in serious bacterial infections. Journal of Antimicrobial Chemotherapy 1995;36(Suppl A):145–56. Muller 1987 {published data only} Muller EL, Pitt HA, Thompson JE Jr, Doty JE, Mann LL, Manchester B. Antibiotics in infections of the biliary tract. Surgery, gynecology & obstetrics 1987;165(4):285–92. Naime Libien 1992 {published data only} Naime Libien J, Vigueras Rendon A, Sanchez Diaz G, Abraham Jalil A. Clinical study to evaluate efficacy and safety of ceftizoxime compared vs penicillin-gentamicin fixed combination in the treatment of severe respiratory infections [Estudio clinico para determinar la eficacia y seguridad de ceftizoxima en comparacion con la asociacion penicilina gentamicina en el tratamiento de las infecciones respiratorias graves]. Compend Invest Clin Latinoam 1992;12(2):42–8. Piccart 1984 {published data only (unpublished sought but not used)} Piccart M, Klastersky J, Meunier F, Lagast H, Van Laethem Y, Weerts D. Single-drug versus combination empirical therapy for gram-negative bacillary infections in febrile cancer patients with and without granulocytopenia. Antimicrobial Agents and Chemotherapy 1984;26 (6):870–5. Rapp 1984 {published data only} Rapp RP, Young B, Foster TS, Tibbs PA, O’Neal W. Ceftazidime versus tobramycin/ticarcillin in treating hospital acquired pneumonia and bacteremia. International Conference on Antimicrobial Agents and Chemotherapy. 1983. ∗ Rapp RP, Young B, Foster TS, Tibbs PA, O’Neal W. Ceftazidime versus tobramycin/ticarcillin in treating hospital acquired pneumonia and bacteremia. Pharmacotherapy 1984;4(4):211–5. Rasmussen 1986 {published and unpublished data} Rasmussen D, Bremmelgaard A, Rasmussen F, Thorup J. Treatment of serious urological infections with cefotaxime compared to ampicillin plus netilmicin. Danish Medical Bulletin 1986;33(1):49–51. Ribera 1996 {published and unpublished data} Ribera E, Gomez-Jimenez J, Cortes E, del Valle O, Planes A, Gonzalez-Alujas T, et al.Effectiveness of cloxacillin with and without gentamicin in short-term therapy for right-sided Staphylococcus aureus
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endocarditis. A randomized, controlled trial. Annals of Internal Medicine 1996;125(12):969–74. Rubinstein 1995 {published and unpublished data} Rubinstein E, Lode H, Grassi C, Castelo A, Ward K, Alanko K et al (Antibiotic Study Group). Ceftazidime monotherapy vs. Ceftriaxone/tobramycin for serious hospital- acquired gram-negative infections.. Clinical Infectious Diseases 1995;20(5):1217–28. Sage 1987 {published data only} Sage R, Nazareth B, Noone P. A prospective randomised comparison of cefotaxime vs. netilmicin vs. cefotaxime plus netilmicin in the treatment of hospitalised patients with serious sepsis. Scandinavian Journal of Infectious Diseases 1987;19(3):331–7. Sandberg 1997 {published and unpublished data} Sandberg T, Alestig K, Eilard T, Ek E, Hebelka M, Johansson E, et al.Aminoglycosides do not improve the efficacy of cephalosporins for treatment of acute pyelonephritis in women. Scandinavian Journal of Infectious Diseases 1997;29(2):175–9. Sanfilippo 1989 {published data only} Sanfilippo JS, Schikler KN. Mezlocillin versus penicillin and tobramycin in adolescent pelvic inflammatory disease: A prospective study. International Pediatrics 1989;4(1):53–6. Sculier 1982 {published data only (unpublished sought but not used)} Sculier JP, Coppens L, Klastersky J. Effectiveness of mezlocillin and endotracheally administered sisomicin with or without parenteral sisomicin in the treatment of Gram-negative bronchopneumonia. Journal of Antimicrobial Chemotherapy 1982;9(1):63–8. Sexton 1998 {published data only} Sexton DJ, Tenenbaum MJ, Wilson WR, Steckelberg JM, Tice AD, Gilbert D, et al.Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Endocarditis Treatment Consortium Group. Clinical Infectious Diseases 1998;27 (6):1470–4. Sieger 1997 {published data only} ∗ Sieger B, Berman SJ, Geckler RW, Farkas SA, for the Meropenem Lower Respiratory Infection Group. Empiric treatment of hospital-acquired lower respiratory tract infections with meropenem or ceftazidime with tobramycin: a randomized study. Critical Care Medicine 1997;25(10):1663–70. Sieger B, Geckler RW. A comparison of meropenem and ceftazidime plus tobramycin in the treatment of hospital-acquired lower respiratory tract infections. 33rd Interscience Conference on Antimicrobials Agents and Chemotherapy. 1993; Vol. Abstract no. 640:236. Smith 1984 {published data only (unpublished sought but not used)} Moore RD, Smith CR, Holloway JJ, Lietman PS. Cefotaxime vs nafcillin and tobramycin for the treatment of serious infection. Comparative cost-effectiveness. Archives of Internal Medicine 1986;146 (6):1153–7. Moore RD, Smith CR, Lietman PS. Increased risk of renal dysfunction due to interaction of liver disease and aminoglycosides. American Journal of Medicine 1986;80(6):1093–7. ∗ Smith CR, Ambinder R, Lipsky JJ, Petty BG, Israel E, Levitt R, et al.Cefotaxime compared with nafcillin plus tobramycin for serious bacterial infections. A randomized, double-blind trial. Annals of Internal Medicine 1984;101(4):469–77.
Speich 1998 {published and unpublished data} Speich R, Imhof E, Vogt M, Grossenbacher M, Zimmerli W. Efficacy, safety, and tolerance of piperacillin/tazobactam compared to coamoxiclav plus an aminoglycoside in the treatment of severe pneumonia. European Journal of Clinical Microbiology and Infectious Diseases 1998;17(5):313–17. Stille 1992 {published data only} Stille W, Shah PM, Ullmann U, Hoffstedt B, Kreisl C, Bommersbach B et al. For the German and Austrian Imipenem/Cilastatin Study Group. Randomized multicenter clinical trial with imipenem/cilastatin versus cefotaxime/gentamicin in the treatment of patients with non-life-threatening infections. European Journal of Clinical Microbiology and Infectious Diseases 1992;11(8):683–92. Sukoh 1994 {published and unpublished data} Sukoh M, Inoue T, Morita Y, Ito K, Togano Y, Yamanaka K, et al.[Clinical evaluation of combination therapy of sulbactam/cefoperazone and aminoglycoside in respiratory tract infections]. In Japanese. Japanese Journal of Antibiotics 1994;47(2):170–80. Takamoto 1994 {published data only} Takamoto M, Ishibashi T, Toyoshima H, Tanaka H, Tamaru N, Watanabe K, et al.[Imipenem/cilastatin sodium alone or combined with amikacin sulfate in respiratory infections]. In Japanese. Japanese Journal of Antibiotics 1994;47(9):1131–44. Thompson 1990 {published data only} Thompson JE Jr, Pitt HA, Doty JE, Coleman J, Irving C. Broad spectrum penicillin as an adequate therapy for acute cholangitis. Surgery, gynecology & obstetrics 1990;171(4):275–82. Thompson 1993 {published data only} Thompson JE Jr, Bennion RS, Roettger R, Lally KP, Hopkins JA, Wilson SE. Cefepime for infections of the biliary tract. Surgery, gynecology & obstetrics 1993;177(Suppl):30–4. Trujillo 1992 {published data only} Zavala Trujillo I. Research on efficacy and safety of ceftizoxime in treating lower respiratory tract and skin and soft tissues infections [Busqueda de la eficacia y seguridad de ceftizoxima en el tratamiento de infecciones del tracto respiratorio inferior y de la piel y de los tejidos blandos]. Compend Invest Clin Latinoam 1992;12(2):31–41. Vergnon 1985 {published data only} Vergnon JM, Vincent M, Ros A, Brun Y, Brune J. [Comparative clinical trial of cefoperazone versus ampicillin + tobramycin in severe bronchopulmonary and pleural infectious pathology]. In French. Revue de pneumologie clinique 1985;41(3):205–11. Verzasconi 1995 {published data only} Verzasconi R, Rodoni P, Monotti R, Marone C, Mombelli G. [Amoxicillin and clavulanic acid versus amoxicillin plus gentamicin in the empirical initial treatment of urinary tract infections in hospitalized patients] [In German]. Schweizerische medizinische Wochenschrift 1995;125(33):1533–9. Warren 1983 {published data only} Warren JW, Miller EH Jr, Fitzpatrick B, DiFranco DE, Caplan ES, Tenney JH, et al.A randomized, controlled trial of cefoperazone vs. cefamandole- tobramycin in the treatment of putative, severe infections with gram- negative bacilli. Reviews in Infectious Diseases 1983; 5(Suppl 1):S173–S180.
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Wiecek 1986 {published data only} Wiecek A, Kokot F, Andrzejowska H, Grzeszczak W. [Clinical evaluation of ceftazidime and the combined administration of cefotaxime and tobramycin in the treatment of urinary tract infections. Prospective and randomized studies] In Polish. Polski tygodnik lekarski 1986; 41(39):1242–46. Wing 1998 {published and unpublished data} Wing DA, Hendershott CM, Debuque L, Millar LK. A randomized trial of three antibiotic regimens for the treatment of pyelonephritis in pregnancy. Obstetrics and gynecology 1998;92(2):249–53. Yellin 1993 {published and unpublished data} Yellin AE, Berne TV, Appleman MD, Heseltine PN, Gill MA, Okamoto MP, et al.A randomized study of cefepime versus the combination of gentamicin and mezlocillin as an adjunct to surgical treatment in patients with acute cholecystitis. Surgery, gynecology & obstetrics 1993;177(Suppl):23–9.
References to studies excluded from this review Alvarez-Lerma 2001b {published data only} Alvarez-Lerma F, Insausti-Ordenana J, Jorda-Marcos R, MaraviPoma E, Torres-Marti A, Nava J, et al.Efficacy and tolerability of piperacillin/tazobactam versus ceftazidime in association with amikacin for treating nosocomial pneumonia in intensive care patients: a prospective randomized multicenter trial. Intensive Care Medicine 2001;27(3):493–502. Badaro 2002 {published data only} Badaro R, Molinar F, Seas C, Stamboulian D, Mendonca J, Massud J, et al.A multicenter comparative study of cefepime versus broadspectrum antibacterial therapy in moderate and severe bacterial infections. Brazilian Journal of Infectious Diseases 2002;6(5):206–18. Benlloch 1995 {published data only} Benlloch C, Costa E, Segarra V, Velazquez JA, Ruiz CS. Systemic antibiotherapy in acute appendicitis. Comparison of three antibiotic regimes [Antibioterapia sistemica en apendicitis aguda. Comparacion entre tres pautas antibioticas]. Acta Pediatrica Espanola 1995; 53(6):367–9. Blumer 2003 {published data only} ∗ Blumer JL, Minkwitz M, Saiman L, San Gabriel P, Iaconis J, Melnick D. Meropenem (MEM) compared with ceftazidime (CAZ) in combination with tobramycin (TOB) for treatment of actue pulmonary exacerbations (APE) in patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa (PA) or burkholderia cepacia (BC). Pediatric Pulmonology. 2003; Vol. Suppl 25:294. Cetto 1983 {published data only} Cetto GL, Todeschini G, Caramaschi G, Vinante F, Benini F, Perona G. Empiric therapy of infections in hematologic malignancies: a prospective, randomized trial. Tumori 1983;69(2):155–60. Ciftci 1997 {published data only} Ciftci AO, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Comparative trial of four antibiotic combinations for perforated appendicitis in children. European Journal of Surgery 1997;163(8):591–6. Crenshaw 1983 {published data only} Crenshaw C, Glanges E, Webber C, McReynolds DB. A prospective random study of a single agent versus combination antibiotics as
therapy in penetrating injuries of the abdomen. Surgery Gynecology & Obstetrics 1983;156(3):289–94. Croce 1993 {published data only} Croce M, Fabian TC, Stewart RM, Pritchard FE, Minard G, Trenthem L, et al.Empiric monotherapy versus combination therapy of nosocomial pneumonia in trauma patients. The Journal of Trauma 1993;35(2):303–9. De Louvois 1992 {published data only} De Louvois J, Dagan R, Tessin I. A comparison of ceftazidime and aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn. European Society for Paediatric Infectious Diseases--Neonatal Sepsis Study Group. European Journal of Pediatrics 1992;151(12):876–84. Extermann 1995 {published data only} Extermann M, Regamey C, Humair L, Murisier F, Rhyner K, Vonwiller HM. Initial Treatment of Sepsis in Non-Neutropenic Patients - Ceftazidime Alone Versus Best Guess Combined Antibiotic-Therapy. Chemotherapy 1995;41:306–15. Fainstein 1983 {published data only} Fainstein V, Bodey GP, Elting L, Bolivar R, Keating MJ, McCredie KB, et al.A randomized study of ceftazidime compared to ceftazidime and tobramycin for the treatment of infections in cancer patients. Journal of Antimicrobial Chemotherapy 1983;12 Suppl A:101–10. Fernandez 1991 {published data only} Fernandez GM, Gudiol F, Rodriguez TA, Arnau C, Valdes L, Vallve C. Nosocomial pneumonia: comparative multicentre trial between monotherapy with cefotaxime and treatment with antibiotic combinations. Infection 1991;19(Suppl 6):S320–S325. Foord 1985 {published data only} Foord RD. Aspects of clinical trials with ceftazidime worldwide. American Journal of Medicine 1985;79(2A):110–3. Gentry 1980 {published data only} Gentry LO, Wood BA, Martin MD, Smythe J. Cefamandole alone and combined with gentamicin or tobramycin in the treatment of acute pyelonephritis. Scandinavian Journal of Infectious Diseases 1980;suppl(25):96–100. Gentry 1984 {published data only} Gentry LO, Feliciano DV, Lea AS, Short HD, Mattox KL, Jordan GL Jr. Perioperative antibiotic therapy for penetrating injuries of the abdomen. Annals of Surgery 1984;200(5):561–6. Gentry 1985 {published data only} Gentry LO. Treatment of skin, skin structure, bone, and joint infections with ceftazidime. American Journal of Medicine 1985;79(2A): 67–74. Gerber 1989 {published data only} Gerber B, Retzke F, Wilken H. [Effectiveness of perioperative preventive use of antibiotics with ampicillin/gentamycin or cefotiam in abdominal cesarean section]. Zentralbl Gynakol 1989;111(10):658– 63. Gilbert 1998 {published data only} Gilbert DN, Lee BL, Dworkin RJ, Leggett JL, Chambers HF, Modin G, et al.A randomized comparison of the safety and efficacy of oncedaily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate. American Journal of Medicine 1998;105(3): 182–191.
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Giraud 1989 {published data only} Giraud JR, Chartier M, Ciraru Vigneron N, Becue J, Landes P, Leng JJ, et al.[A comparison of the efficacy of and tolerance to Augmentin used alone and as one of three drugs used to treat acute upper genital tract infections. Results of a multicentre trial 152 cases] [Comparaison de l’efficacite et de la tolerance de l’Augmentine en monotherapie versus triple association dans le traitment des infections genitales hautes aigues. Resultats d’une etude multicentrique portant sur 152 cas]. Contracept Fertil Sex 1989;17(10):941–8.
Hoogkamp 1983 {published data only} Hoogkamp-Korstanje JA, van der Laag J. Piperacillin and tobramycin in the treatment of Pseudomonas lung infections in cystic fibrosis. Journal of Antimicrobial Chemotherapy 1983;12(2):175–83.
Gold 1985 {published data only} Gold R, Overmeyer A, Knie B, Fleming PC, Levison H. Controlled trial of ceftazidime vs. ticarcillin and tobramycin in the treatment of acute respiratory exacerbations in patients with cystic fibrosis. Pediatric Infectious Disease 1985;4(2):172–7.
Iakovlev 2000 {published data only} Iakovlev SV, Dvoretskii LI, Shakhova TV. [The clinical efficacy of ticarcillin/clavulanate in severe pneumonia]. Antibiotiki i Khimioterapia 2000;45(3):30–4.
Gomez 1990b {published data only} Gomez J, Moldenhauer F, Ruiz Gomez J, Ros CM, Martinez Hernandez J, Canteras M, et al.Monotherapy versus antibiotic combinations in bacteremias in an internal medicine department. A prospective study in 1987 [Monoterapia frente a combinaciones antibioticas en las bacteriemias de un departamento de medicina interna. estudio prospectivo durante 1987]. Revista Espanola de Microbiologia Clinica 1990;5(2):89–93. Greco 1989 {published data only} Greco T. Treatment of nosocomial pneumonia: monotherapy versus combination therapy. Geriatrics 1989;44 Suppl A:28–31. Gribble 1983 {published data only} Gribble MJ, Chow AW, Naiman SC, Smith JA, Bowie WR, Sacks SL, et al.Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin-aminoglycoside combination regimens in the empirical treatment of serious bacterial infections. 21st Interscience Conference on Antimicrobial Agents and Chemotherapy. 1981. ∗ Gribble MJ, Chow AW, Naiman SC, Smith JA, Bowie WR, Sacks SL, et al.Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin-aminoglycoside combination regimens in the empirical treatment of serious bacterial infections. Antimicrobial Agents and Chemotherapy 1983;24(3):388–93. Haffejee 1984 {published data only} Haffejee IE. A therapeutic trial of cefotaxime versus penicillin-gentamicin for severe infections in children. Journal of Antimicrobial Chemotherapy 1984;14 Suppl B:147–52. Hall 1988 {published data only} Hall MA, Ducker DA, Lowes JA, McMichael J, Clarke P, Rowe D, et al.A randomised prospective comparison of cefotaxime versus netilmicin/penicillin for treatment of suspected neonatal sepsis. Drugs 1988;35(Suppl 2):169–77. Hammerberg 1989 {published data only} Hammerberg O, Kurnitzki C, Watts J, Rosenbloom D. Randomized trial using piperacillin versus ampicillin and amikacin for treatment of premature neonates with risk factors for sepsis. European Journal of Clinical Microbiology and Infectious Diseases 1989;8(3):241–4. Hanson 1982 {published data only} Hanson B, Coppens L, Klastersky J. Comparative studies of ticarcillin and mezlocillin plus sisomicin in Gram-negative bacillary bacteraemia and bronchopneumonia. Journal of Antimicrobial Chemotherapy 1982;10(4):335–41.
Iakovlev 1997 {published data only} Iakovlev SV, Shakhova TV, Dvoretskii LI, Romanovskii I, Eremina LV, Koroleva TA, et al.[Use of piperacillin/tazobactam as empirical monotherapy in the treatment of bacterial infections in a resuscitation department]. Antibiotiki i Khimioterapia 1997;42(2):33–7.
Ker 1989 {published data only} Ker CG, Hou MF, Chen JS, Lee KT, Sheen PC, Akbary MA. A comparative study of cefotaxime sodium versus a combination of cefapirin and gentamicin in the prophylactic treatment of patients undergoing cholecystectomy. Methods and Findings in Experimental and Clinical Pharmacology 1989;11(11):711–5. Krumpe 1999 {published data only} Krumpe PE, Cohn S, Garreltes J, Ramirez J, Coulter H, Haverstock D, et al.Intravenous and oral mono- or combination-therapy in the treatment of severe infections: ciprofloxacin versus standard antibiotic therapy. Ciprofloxacin Study Group. Journal of Antimicrobial Chemotherapy 1999;43(Suppl A):117–28. Ludwig 1980 {published data only} Ludwig G, Knebel L. Cefotaxime in urinary tract infections--comparative clinical studies with gentamicin and with cefoxitin. Journal of Antimicrobial Chemotherapy 1980;6 Suppl A:207–11. Maller 1991 {published data only} Maller R, Ahrne H, Eilard T, Eriksson I, Lausen I. Efficacy and safety of amikacin in systemic infections when given as a single daily dose or in two divided doses. Scandinavian Amikacin Once Daily Study Group. Journal of Antimicrobial Chemotherapy 1991;27(Suppl C): 121–8. Mangi 1988 {published data only} Mangi RJ, Greco T, Ryan J, Thornton G, Andriole VT. Cefoperazone versus combination antibiotic therapy of hospital-acquired pneumonia. American Journal of Medicine 1988;84(1):68–74. McArdle 1987 {published data only} McArdle C, Morran C, Greig J, Mason B, Haddock G, Sleigh J, et al.Comparison of cefotetan and gentamicin/ampicillin in high-risk biliary tract surgery. Chemioterapia 1987;6(2 Suppl):593–4. McCarty 1988 {published data only} McCarty JM, Tilden SJ, Black P, Craft JC, Blumer J, Waring W, et al.Comparison of piperacillin alone versus piperacillin plus tobramycin for treatment of respiratory infections in children with cystic fibrosis. Pediatric Pulmonology 1988;4(4):201–4. McLaughlin 1983 {published data only} McLaughlin FJ, Matthews WJ, Jr, Strieder DJ, Sullivan B, Goldmann DA. Randomized, double-blind evaluation of azlocillin for the treatment of pulmonary exacerbations of cystic fibrosis. Journal of Antimicrobial Chemotherapy 1983;11(Suppl B):195–203. ∗ McLaughlin FJ, Matthews WJ Jr, Strieder DJ, Sullivan B, Taneja A, Murphy P, Goldmann DA. Clinical and bacteriological responses
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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to three antibiotic regimens for acute exacerbations of cystic fibrosis: ticarcillin-tobramycin, azlocillin-tobramycin, and azlocillin-placebo. Journal of Infectious Diseases 1983;147(3):559–567. Mondorf 1987 {published data only} Mondorf A, Mondorf W, Banzer S. A multiple-center comparative study of the kidney tolerance of ceftazidime versus cefotaxime and tobramycin. Chemioterapia 1987;6(2 Suppl):331–2. Mondorf 1989 {published data only} Mondorf AW, Bonsiepe C, Mondorf W. Randomized multi center study comparing nephrotoxicity of ceftazidime versus the combination of piperacillin and netilmicin with and without furosemide. Advances in Experimental Medicine and Biology 1989;252:307–12. Moreno-Martinez 1998 {published data only} Moreno Martinez A, Mensa J, Martinez JA, Marco F, Vila J, Almela M, et al.Cefixime versus amoxicillin plus netilmicin in the treatment of community-acquired non-complicated acute pyelonephritis. Medicina Clinica 1998;111(14):521–4. Mouton 1985 {published data only} Mouton Y, Deboscker Y, Beuscart C, Beaucaire G, Fourrier A. Third generation cephalosporins in combination with aminoglycosides or in monotherapy for life-threatening infections in an intensive care unit. 25th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1985:Abstract no. 958. Oblinger 1982 {published data only} Oblinger MJ, Bowers JT, Sande MA, Mandell GL. Moxalactam therapy vs. standard antimicrobial therapy for selected serious infections. Reviews of Infectious Diseases 1982;4(Suppl):S639–S649. Odio 1987 {published data only} Odio CM, Umana MA, Saenz A, Salas JL, McCracken GH. Comparative efficacy of ceftazidime vs. carbenicillin and amikacin for treatment of neonatal septicemia. Pediatric Infectious Diseases Journal 1987;6(4):371–7. Padoan 1987 {published data only} Padoan R, Cambisano W, Costantini D, Crossignani RM, Danza ML, Trezzi G, et al.Ceftazidime monotherapy vs. combined therapy in Pseudomonas pulmonary infections in cystic fibrosis. Pediatric Infectious Diseases Journal 1987;6(7):648–53. Paoletti 1989 {published data only} Paoletti V, Mammarella A, Mariani A, Filippello CP, Franchino L, Barlattani M. Netilmicin in the treatment of infections of the lower urinary tract [La netilimicina nel trattamento delle infeziono delle basse vie urinarie]. Clinical Therapeutics 1989;128(6):405–9. Rodloff 1998 {published data only} Rodloff Ac, Kujath P, Lunstedt B, Gaus W. Comparative study of the cost-effectiveness of initial therapy with imipenem/cilastatin in secondary peritonitis. Chirurgia 1998;69(10):1093–1100. Romanelli 2002 {published data only} Romanelli G, Cravarezza P, Pozzi A, Franchino L, Ravizzola G, Zulli R, et al.Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy. Journal of Chemotherapy 2002;14(6):609– 17. Schoengut 1983 {published data only} Schoengut H, Jelinek R. Comparative study of the effects of ceftazidime compared with tobramycin plus cefamandole in the treat-
ment of gall bladder empyema. Journal of Antimicrobial Chemotherapy 1983;12 Suppl A:219–22. Schuler 1995 {published data only} Schuler D, and the Meropenem Paediatric Study Group. Safety and efficacy of meropenem in hospitalised children: randomised comparison with cefotaxime, alone and combined with metronidazole or amikacin. Journal of Antimicrobial Chemotherapy 1995;36(Suppl A): 99–108. Scott 1987 {published data only} Scott SD, Saddler B, Lowes JA, Karran SJ. Comparison of cefotetan versus combination therapy in peritonitis and serious intra-abdominal sepsis. Chemioterapia 1987;6(2 Suppl):475–6. Sexton 1984 {published data only} Sexton DJ, Wlodaver CG, Tobey LE, Finn LA, Chubb JM. Ceftazidime therapy for Gram-negative bone and joint infections. 24th Interscience Conference on Antimicrobial Agents and Chemotherapy. 1984; Vol. Abstract no. 1213:305. Sheftel 1986 {published data only} Sheftel TG, Mader JT. Randomized evaluation of ceftazidime or ticarcillin and tobramycin for the treatment of osteomyelitis caused by gram-negative bacilli. Antimicrobial Agents and Chemotherapy 1986; 29(1):112–5. Smith 1999 {published data only} Smith AL, Doershuk C, Goldmann D, Gore E, Hilman B, Marks M, et al.Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis. Journal of Pediatrica 1999;134(4):413–21. Solberg 1995 {published data only} Solberg CO, Sjursen H. Safety and efficacy of meropenem in patients with septicaemia: a randomised comparison with ceftazidime, alone or combined with amikacin. Journal of Antimicrobial Chemotherapy 1995;36(Suppl A):157–66. Solomkin 1986 {published data only} Solomkin JS, Cocchetto DM. Ceftazidime versus tobramycin plus ticarcillin in the treatment of soft-tissue infections. Clinical Therapeutics 1986;9(1):123–34. Stack 1985 {published data only} Stack BHR, Geddes DM, Williams KJ, Dinwiddie R, Selkon JB, Godfrey RC, for the British Thoracic Society Research Committee. Ceftazidime compared with gentamicin and carbenicillin in patients with cystic fibrosis, pulmonary pseudomonas infection, and an exacerbation of respiratory symptoms. Thorax 1985;40(5):358–63. Tally 1986 {published data only} Tally FP, Kellum JM, Ho JL, O’Donnell TF, Barza M, Gorbach SL. Randomized prospective study comparing moxalactam and cefoxitin with or without tobramycin for the treatment of serious surgical infections. Antimicrobial Agents and Chemotherapy 1986;29(2):244– 9. Thompson 1980 {published data only} Thompson SE, Hager WD, Wong KH, Lopez B, Ramsey C, Allen SD, et al.The microbiology and therapy of acute pelvic inflammatory disease in hospitalized patients. American Journal of Obstetrics & Gynecology 1980;136(2):179–86.
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Vazquez 1994 {published data only} Vazquez Vela Sanchez G, De Leon Zavala J, Ochoa Cozares M. Comparative study of two preventive antibiotic programs for treatment of open fractures [Estudio comparativo de dos esquemas de antibioticos para la prevencion de la infeccion en las fracturas expuestas]. Rev mex ortoptraumatol 1994;8(5):263–4. Vetter 1987 {published data only} ∗ Vetter N, Feist H, Armbruster C, Drlicek M. Comparison of the effectiveness of ceftazidime and cefazolin/tobramycin in patients with inflammatory diseases of the lower respiratory tract. In German [Efficacy of ceftazidime and cefazolin/tobramycin in lower respiratory tract infections]. Infection 1987;15(Suppl 4):S192–4. Vetter N, Feist H, Muhar F, Williams KJ. A comparative study of the efficacy of ceftazidime versus cefazolin and tobramycin in patients with acute exacerbations of chronic bronchitis. Journal of Antimicrobial Chemotherapy 1983;12(Suppl A):35–9. Vetter 1992 {published data only} Vetter N. Efficacy of meropenem in the treatment of respiratory tract infection:a comparative evaluation. Proceedings of the Eighth Mediterranean Congress of Chemotherapy. 1992:175. Vetter N. Efficacy of meropenem in the treatment of respiratory tract infection: a comparative evaluation. Journal of Chemotherapy. 1993; Vol. 5 Suppl 1. Watanakunakorn 1997 {published data only} Watanakunakorn C, Baird IM. Prognostic factors in Staphylococcus aureus endocarditis and results of therapy with a penicillin and gentamicin. The American journal of Medical Sciences 1977;273(2): 133–9.
References to studies awaiting assessment Figueroa-Damian 1996 {published data only} Figueroa-Damian R, Villagrana-Zesati R, San Martin-Herrasti JM, Arredondo-Garcia JL. Comparison of the therapeutic efficacy of the piperacillin/tazobactame combination vs. ampicillin and gentamycin in the management of post-cesarean endometritis [Comparación de la eficacia terapéutica de piperacilina\tazobactam vs ampicilina más gentamicina en el tratamiento de endometritis poscesárea]. Ginecologia y Obstetricia de Mexico 1996;64(5):214–8. Luis-Alberto 1999 {published data only} Luis Alberto GR, Enrique RJ, Manuel de Jesus UV, Ana Patricia MB, Jose Javier LN, Jaime MM. Ceftazidime vs crystalline sodium penicillin and amikacin in the treatment of nosocomial pneumonia [Ceftazidima vs penicilina sodica cristalina y amikacina en el manejo de la neumonia nosocomial]. Medicina interna Mexico 1999;15(4): 135–7.
Additional references
Barza 1996 Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996;312(7027): 338–45. Bayer 1998 Bayer AS, Bolger AF, Taubert KA, Wilson W, Steckelberg J, Karchmer AW, et al.Diagnosis and management of infective endocarditis and its complications. Circulation 1998;98(25):2936–48. Bone 1992 Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 1992;101(6):1481–3. Bryant 1971 Bryant RE, Hood AF, Hood CE, Koenig MG. Factors affecting mortality of gram-negative rod bacteremia. Archives of Internal Medicine 1971;127(1):120–8. Elphick 2001 Elphick HE, Tan A. Single versus combination intravenous antibiotic therapy for people with cystic fibrosis (Cochrane Review). In: The Cochrane Library 2004, Issue 3.[Art. No.: CD002007. DOI: 10.1002/14651858.CD002007.pub2] Geerdes 1991 Geerdes HF, Ziegler D, Lode H, Hund M, Loehr A, Fangmann W, et al.Septicemia in 980 patients at a university hospital in Berlin: prospective studies during 4 selected years between 1979 and 1989. Clinical Infectious Diseases 1992;15(6):991–1002. Giamarellou 1984 Giamarellou H, Zissis NP, Tagari G, Bouzos J. In vitro synergistic activities of aminoglycosides and new beta-lactams against multiresistant Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy 1984;25(4):534–6. Giamarellou 1986 Giamarellou H. Aminoglycosides plus beta-lactams against gramnegative organisms. Evaluation of in vitro synergy and chemical interactions. American Journal of Medicine 1986;80(6B):126–37. Higgins 2005 Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]. Appendix 5c.: In: The Cochrane Library, Issue 3, 2005. Chichester, UK: John Wiley & Sons, Ltd. Hilf 1989 Hilf M, Yu VL, Sharp J, Zuravleff JJ, Korvick JA, Muder RR. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients. American Journal of Medicine 1989;87(5):540–6.
Allan 1985 Allan JD, Moellering RC. Management of infections caused by gramnegative bacilli: the role of antimicrobial combinations. Reviews of Infectious Diseases 1985;7 Suppl 4:559–71.
Hughes 2002 Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al.2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clinical Infectious Diseases 2002; 34(6):730–51.
Baine 2001 Baine WB, Yu W, Summe JP. The epidemiology of hospitalization of elderly Americans for septicemia or bacteremia in 1991-1998. Application of Medicare claims data. Annals of Epidemiology 2001; 11(2):118–26.
Ibrahim 2000 Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest 2000;118(1): 146–55.
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Klastersky 1976 Klastersky J, Meunier-Carpentier F, Prevost JM, Staquet M. Synergism between amikacin and cefazolin against Klebsiella: in vitro studies and effect on the bactericidal activity of serum. Journal of Infectious Diseases 1976;134(3):271–6. Klastersky 1982 Klastersky J, Zinner SH. Synergistic combinations of antibiotics in gram-negative bacillary infections. Reviews of Infectious Diseases 1982;4(2):294–301. Leibovici 1997 Leibovici L, Paul M, Poznanski O, Drucker M, Samra Z, Konigsberger H, et al.Monotherapy versus beta-lactam-aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study. Antimicrobial Agents and Chemotherapy 1997; 41(5):1127–33. Leibovici 1998 Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. Journal of Internal Medicine 1998; 244(5):379–86. Mandell 2004 Mandell GL, Bennet JE, Dolin R, editors. Principles and practice of infectious diseases. 6th Edition. Philadelphia: Churchill Livingstone, 2004. Manian 1996 Manian FA, Meyer L, Jenne J, Owen A, Taff T. Loss of antimicrobial susceptibility in aerobic gram-negative bacilli repeatedly isolated from patients in intensive-care units. Infection Control and Hospital Epidemiology 1996;17(4):222–6. Milatovic 1987 Milatovic D, Braveny I. Development of resistance during antibiotic therapy. European Journal of Clinical Microbiology 1987;6(3):234– 44. Moellering 1986 Moellering RC, Jr, Eliopoulos GM, Allan JD. Beta-lactam/aminoglycoside combinations: interactions and their mechanisms. American Journal of Medicine 1986;80(5C):30–4. Moore 2001 Moore RB, Shapiro NI, Wolfe RE, Smith ES, Bermudez S, Bates D. The value of sirs criteria in ed patients with presumed infection in predicting mortality. Academic Emergency Medicine 2001;8(5):477. Paul 2001 Paul M, Soares-Weiser K, Grozinsky S, Leibovici L. Beta-lactam versus beta-lactam-aminoglycoside combination in cancer patients with
neutropenia (Cochrane Review). In: The Cochrane Library 2004, Issue 3. Rangel-Frausto 1995 Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. Journal of the American Medical Association 1995;273(2):117–23. Russell 2000 Russell JA, Singer J, Bernard GR, Wheeler A, Fulkerson W, Hudson L, et al.Changing pattern of organ dysfunction in early human sepsis is related to mortality. Critical Care Medicine 2000;28(10):3405–11. Safdar 2004 Safdar N, Handelsman J, Maki DG. Does Combination Antibiotic therapy Reduce Mortality in Gram-Negative Bacteremia? A metaanalysis.. Lancet Infectious Diseases 2004;4:519–27. Sande 1975 Sande MA, Johnson ML. Antimicrobial therapy of experimental endocarditis caused by Staphylococcus aureus. Journal of Infectious Diseases 1975;131(4):367–75. Sande 1976 Sande MA, Courtney KB. Nafcillin-gentamicin synergism in experimental staphylococcal endocarditis. Journal of Laboratory and Clinical Medicine 1976;88(1):118–24. Schulz 1995 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Medical Association 1995;273(5):408–12. Weinstein 1985 Weinstein L. Gram-negative bacterial infections: a look at the past, a view of the present, and a glance at the future. Reviews of Infectious Diseases 1985;7 Suppl 4:538–44. Whitelaw 1992 Whitelaw DA, Rayner BL, Willcox PA. Community-acquired bacteremia in the elderly: a prospective study of 121 cases. Journal of the American Geriatrics Society 1992;40(10):996–1000.
References to other published versions of this review Paul 2004 Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. BMJ 2004;328(7441):668–72. ∗ Indicates the major publication for the study
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] Abrams 1979 Methods
RCT Empirical and semi-empirical Gram positive infections
Participants
36 IV drug users with suspected Staphylococcal endocarditis were included. Only those with Staphylococcus aureus bacteraemia and endocarditis according to inclusion criteria were evaluated Patients excluded because they did not fulfil inclusion criteria for bacteraemia were not considered as dropouts for the review
Interventions
Oxacillin 12gr/d vs. oxacillin 12gr/d + gentamicin 80mgX3 (gentamicin administered for the first 2 weeks of a 4-week treatment protocol)
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Adverse events Duration of fever
Notes
USA Outcomes in subgroups: Bacteraemia. Cephalothin was permitted instead of oxacillin for patients with penicillin allergy, and oxacillin was replaced by penicillin for penicillin-susceptible Staphylococcus aureus.
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Aguilar 1992 Methods
RCT Sepsis
Participants
36 patients > 16 yrs. with severe infections
Interventions
Ceftizoxime 60-150 mg/kg/d vs. penicillin 20-30mU/d + gentamicin 3-5mg/kg/d
Outcomes
Treatment failure (clinical and bacteriological)
Notes
Mexico No outcomes in subgroups
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Aguilar 1992
(Continued)
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Alvarez-Lerma 2001a Methods
RCT Sepsis
Participants
140 adult patients hospitalized in the ICU, mechanically ventilated and diagnosed with pneumonia. All infections were hospital acquired. 66% of patients were on inotropic drugs upon entry to study
Interventions
Meropenem 1grX3 for 9.3 days vs. ceftazidime 2grX3 + amikacin 7.5mg/kgX2 for 8.3 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Bacterial superinfections Adverse events Duration of treatment
Notes
Multicentre Spain Outcomes in subgroups: Gram negative and Pseudomonas sp. infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Arich 1987 Methods
RCT Partially semi-empirical Sepsis
Participants
Adult patients with enterobacteriacae bacteraemia (at least 2 positive blood cultures with same pathogen). Patients could enter the trial before or at diagnosis of bacteraemia
Interventions
Cefotaxime 1grX3-4 for 17.5 days vs. cefazolin 1grX3 + tobramycin 1.5mg/kgX3 for 10 days
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
31
Arich 1987
(Continued)
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfection Adverse events Duration of hospitalizations, treatment and fever
Notes
France (French) Outcomes in subgroups: Bacteraemia Gram-negative infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Bergeron 1988 Methods
RCT Abdominal
Participants
77 adult patients with severe biliary tract infections (cholecystitis, cholangitis and necrotizing cholecystitis)
Interventions
Cefoperazone 2grX2 for 7.2 days vs. ampicillin 1grX4 + tobramycin 1.5mg/kgX3 following loading dose 2mg/kg for 6.8 days (Surgery in addition to medical treatment was performed in 28/36 monotherapy patients and in 19/29 combination patients, not counted as failure)
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfections Colonization Treatment duration Dropouts Adverse events
Notes
Multicentre Canada Outcomes in subgroups: Bacteraemia
Risk of bias Item
Authors’ judgement
Description
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
32
Bergeron 1988
(Continued)
Allocation concealment?
Unclear
B - Unclear
Biglino 1991 Methods
RCT Sepsis
Participants
22 patients with severe infections. Patients were compromised by background diseases, including some immunecompromise in 73%. Randomized to 4 arms monotherapy vs. combination, and high vs. low dose of imipenem
Interventions
Imipenem 0.5-1grX4 vs. imipenem 0.5-1grX4 + netilmicin 5mg/kg
Outcomes
Treatment failure (clinical) Adverse events Duration of fever and hospital stay
Notes
Italy No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Brown 1984 Methods
RCT Sepsis
Participants
48 adult patients (34 evaluated) with hospital acquired pneumonia of a documented Gram-negative origin (By sputum’s Gram stain or cultures). 85% (29/34) acquired infection in the ICU
Interventions
Moxalactam 2grX3 for 10.1 days vs. carbenicillin 66mg/kgX6 + tobramycin 1.7mg/kgX3 (following a 2-2.5mg/kg loading dose) for 10.6 days
Outcomes
Overall mortality Treatment failure (x-ray non-clearing) Superinfections Adverse events Duration of treatment
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
33
Brown 1984
(Continued)
Notes
USA Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections 4 deaths among 11 excluded patients not included in outcome assessment
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Carbon 1987 Methods
RCT Probably semi-empirical Sepsis
Participants
74 patients with bacteraemia due to enterobacteriaceae, with at least 3 positive blood cultures entered the study
Interventions
Cefotaxime 1grX4 for 12.9 days vs. cefotaxime 1grX4 + amikacin 7.5mg/kg loading dose followed by a renal-function adjusted maintenance dose for 13.2 days
Outcomes
Overall mortality Treatment failure (clinical) Superinfections Adverse events Duration of treatment and fever
Notes
Multicentre France Outcomes in subgroups: Gram negative infections Bacteraemia
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
34
Cardozo 2001 Methods
RCT Abdominal
Participants
110 children 38 lasting > 8 hours. 88% of patients with underlying haematological malignancy
Interventions
Ceftriaxone 2grX1 for a median of 12 days vs. ceftriaxone 2grX1 + amikacin 5mg/kgX3 for a median of 11 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfection and colonization (bacterial and fungal) Adverse events Treatment duration
Notes
Italy Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections Bacteraemia Urinary tract infection
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
37
Duff 1982 Methods
Quasi-randomized Abdominal
Participants
74 patients included who developed endomyoparametritis after caesarian section or vaginal delivery, or who developed pelvic cellulitis after hysterectomy
Interventions
Cefoxitin 2grX3 vs. penicillin 5millUX4 + gentamicin 60-80mgX3
Outcomes
Overall mortality Treatment failure Adverse events Dropouts
Notes
USA Outcomes in subgroups: Gram-negative infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
No
C - Inadequate
Dupont 2000 Methods
RCT Abdominal
Participants
227 patients evaluated with severe generalized peritonitis Modified ITT analysis was performed on 204 patients with surgically proven severe intra-abdominal infections
Interventions
Piperacillin- tazobactam 4grX4 for 8.2 days vs. piperacillin- tazobactam 4grX4 + amikacin 7.5mg/kgX2 for 8.6 days. In addition all patients were operated on
Outcomes
Overall mortality Treatment failure (clinical) Adverse events Dropouts Treatment duration
Notes
Multicentre France No outcomes in subgroups
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
38
Dupont 2000
(Continued)
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Felisart 1985 Methods
RCT Sepsis
Participants
73 adult patients with underlying advanced cirrhosis, presenting with severe bacterial infections. Most patients had spontaneous bacterial peritonitis
Interventions
Cefotaxime 2grX6 vs. ampicillin 2grX6 + tobramycin renal adjusted maintenance dose X3/d following 1.75mg/kg loading dose
Outcomes
Overall mortality Treatment failure (clinical) Superinfections Adverse events
Notes
Spain Outcomes in subgroups: Bacteraemia Urinary tract infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Finer 1992 Methods
RCT Sepsis
Participants
471 adult patients hospitalized with signs and symptoms of serious bacterial infections, thought by the physician to require parenteral antibiotic treatment
Interventions
Ceftazidime 2grX2 vs. ureidopenillin + aminoglycoside used routinely in specific Center: piperacillingentamicin (73p); ampicillingentamicin (69p); mezlocillinnetilmicin (44p); piperacillin-
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
39
Finer 1992
(Continued) netilmicin (20p)
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfections Colonization Drop-outs after randomisation Adverse events
Notes
Multicentre UK Outcomes in subgroups: Bacteraemia
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Gerecht 1989 Methods
RCT Abdominal
Participants
82 patients with suspected cholangitis were randomized empirically. Only those with bacteraemia or positive bile cultures, and fulfilling clinical criteria for cholangitis were evaluated. Patients who were not evaluated because they did not meet inclusion criteria are not considered as dropouts for the review
Interventions
Mezlocillin 4grX4 for 11.9 days vs. ampicillin 1grX4 + gentamicin 1.5mg/kgX3 for 10.3 days. In addition to antibiotic therapy all patients underwent surgical intervention
Outcomes
Treatment failure (clinical and bacteriological) Superinfections Adverse events Duration of treatment
Notes
USA No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
40
Gomez 1990a Methods
RCT Sepsis
Participants
197 patients with suspected Gram-negative bacteraemia randomized. Patients with proven Gram-negative bacteraemia (78) were analysed. Patients who were not evaluated because they did not meet inclusion criteria for bacteraemia were not considered as dropouts
Interventions
Ceftazidime 1grX4 for 10 days vs. cefradine 1grX6 + amikacin 7.5mg/kgX2 for 10 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfection (bacterial and fungal) Adverse events Duration of treatment
Notes
Spain (Spanish) Outcomes in subgroups: Bacteremia Gram-negative infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Havig 1973 Methods
RCT Abdominal
Participants
68 adult patients evaluated with acute cholecystitis verified histologically or by roengten. Trial included 3 arms, of which 2 are included in the review
Interventions
IM ampicillin 0.5grX4 vs. IM chloramphenicol 1grX2 (arm not included in review) vs. IM benzyl-penicillin 400,000IEX2 + IM streptomycin 0.5grX2. In addition 10/24 patients in the ampicillin arm and 15/26 patients in the combination arm were operated on
Outcomes
Overall mortality Treatment failure (clinical) Duration of fever
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
41
Havig 1973
(Continued)
Notes
Norway No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Hoepelman 1988 Methods
RCT Sepsis
Participants
105 patients with serious bacterial infections were included. Of these 18% were neutropenic and are not included for the analysis in this review
Interventions
Ceftriaxone 2grX1 vs. cefuroxime 1.5grX3 + gentamicin 80mgX3 (following by an initial 1.5mg/kg dose)
Outcomes
Overall mortality Treatment failure (clinical) Superinfections Fungal colonization Adverse events
Notes
Netherlands Outcomes for subgroups were not extracted, as they are given in the publication for the whole group including neutropenic patients Outcomes for non-neutropenic patients were obtained from the author
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Holloway 1985 Methods
RCT Sepsis Semi-empirical
Participants
43 adult patients with suspected Gram-negative septicaemia, or pneumonia, randomized when blood cultures were positive for a Gram-negative pathogen
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
42
Holloway 1985
(Continued)
Interventions
Ticarcillin-clavulanic acid 3.1grX4-6 vs. piperacillin 50mg/kgX4-6 + tobramycin 1-1.5mg/kgX3-4
Outcomes
Treatment failure (clinical and bacteriological) Adverse events
Notes
USA Outcomes in subgroups: Bacteremia Gram-negative infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Iakovlev 1998 Methods
RCT Sepsis
Participants
95 adult patients with severe nosocomial infections
Interventions
Meropenem 1grX3 for 9 days vs. ceftazidime 1grX3 + amikacin 500mgX2 for 9 days
Outcomes
Treatment failure (clinical and bacteriological) Duration of treatment Adverse events
Notes
Multicentre Russia (Russian) Outcomes in subgroups: Urinary tract and Pseudomonas sp. infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
43
Jaspers 1998 Methods
RCT Sepsis
Participants
79 elderly patients ( > 65yrs.) with sepsis syndrome and suspected bacteraemia, pneumonia, intra-abdominal sepsis, or complicated urinary tract infection
Interventions
Meropenem 1grX3 for 7.5 days vs. cefuroxime 1.5grX3 + gentamicin 4mg/kgX1 for 7.4 days (metronidazole 500mgX4 added to patients receiving combination in case of abdominal sepsis (15 patients overall)
Outcomes
Overall mortality Treatment failure (clinical and microbiological) Bacterial superinfections Adverse events Duration of treatment
Notes
Multicentre Netherlands Outcomes in subgroups: Urinary tract infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Klastersky 1973 Methods
RCT Sepsis
Participants
75 adult patients with disseminated cancer and life threatening infections, presumed Gram-negative. Randomized to 3 arms, of which 2 are relevant for the review. 18% of patients leukopenic (leukopenia not defined) - no information for neutropenia
Interventions
Carbenicillin 10grX3 for 8.3 days vs. carbenicillin 10grX3 + gentamicin 160mgX3 (IM or IV) for 9 days vs. gentamicin 160mgX3 (3rd arm, not included in review)
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Colonization and Superinfection Duration of treatment Dropouts
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
44
Klastersky 1973
(Continued)
Notes
Belgium Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections Bacteremia Urinary tract infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Kljucar 1990 Methods
RCT Sepsis
Participants
150 patients > 14yrs. hospitalized in the intensive care unit and ventilated, with nosocomially acquired pneumonia. Randomized to 3 arms (2 combination and 1 monotherapy)
Interventions
Ceftazidime 2grX3 vs. ceftazidime 2grX3 + tobramycin 80mgX3 vs. azlocillin 5mgX3 + tobramycin 80mgX3, overall for 6.6 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological)
Notes
Germany No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Koehler 1990 Methods
RCT Sepsis
Participants
144 patients > 18 yrs. with nosocomially acquired pneumonia
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
45
Koehler 1990
(Continued)
Interventions
Ceftazidime 1grX3 vs. piperacillin 4grX3 + tobramycin 80mgX3
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Bacterial and fungal colonization Dropouts
Notes
Multicentre Germany Outcomes in subgroups: Gram negative and Pseudomonas sp. infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Korzeniowski 1982 Methods
RCT Partially semi-empirical Gram positive infections
Participants
156 patients with clinically suspected infective endocarditis were randomized (prior antibiotic treatment of < 48 hours permitted) 78 patients with Staphylococcus aureus bacteremia and endocarditis were analysed: 48 drug addicts and 30 non-addicts (14 patients randomized semi-empirically)
Interventions
Nafcillin 1.5-6grX6 vs. nafcillin 1.5-6grX6 + gentamicin 1mg/kgX3 administered for the first 2 weeks of a 4-week treatment protocol
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Dropouts Need for surgery Adverse events Duration of bacteremia and fever are other outcomes shown in the study, but these are shown by groups of empirical treatment regimen which was not always randomly allocated
Notes
Multicentre USA Outcomes in subgroups: Bacteremia
Risk of bias
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
46
Korzeniowski 1982
(Continued)
Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Landau 1990 Methods
Quasi-randomized Urinary tract infections
Participants
40 adult patients hospitalized with complicated urinary tract infection
Interventions
Ceftriaxone 2grX1 vs. cefazolin 1grX3 + gentamicin 80mgX3
Outcomes
Overall mortality Treatment failure (bacteriological only) Adverse events Drop-outs after randomization Duration of fever
Notes
Israel (Hebrew) Outcomes in subgroups: Urinary tract and Gram-negative infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
No
C - Inadequate
Limson 1988 Methods
RCT Sepsis
Participants
54 adult patients randomized, of which 40 patients with severe Gram-negative infections were evaluated
Interventions
Ceftazidime 2grX2 vs. ticarcillin 3grX3-4 + amikacin 500mgX2 (or 15mg/kgX1)
Outcomes
Treatment failure (clinical and microbiological) Fungal superinfections Adverse events
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
47
Limson 1988
(Continued)
Notes
The Philippines Outcomes in subgroups: Bacteremia Gram negative, and Pseudomonas sp. infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Mandell 1987 Methods
RCT Sepsis
Participants
110 patients > 16yrs. evaluated with community acquired or nosocomial pneumonia (2/3 nosocomial)
Interventions
Ceftazidime 2grX3 vs. cefazolin 1.5grX3 or ticarcillin 3grX4 + tobramycin 1.7mg/kgX3
Outcomes
Treatment failure (clinical and bacteriological) Superinfections Colonization (including resistant development) Adverse events
Notes
Multicentre Canada Outcomes in subgroups: Bacteraemia Gram-negative infections. Cefazolin replaced by ticarcillin for combination group patients with documented Pseudomonas infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Martin 1991 Methods
RCT Urinary tract infections
Participants
116 patients hospitalized with suspected pyelonephritis
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
48
Martin 1991
(Continued)
Interventions
Ceftriaxone 2grX1 vs. ampicillin 1grX4 + gentamicin 1mg/kgX3
Outcomes
Treatment failure (clinical) Superinfection (relapse and re-infections) Dropouts Adverse events
Notes
Brussels (French) Outcomes in subgroups: Urinary tract infections Bacteremia
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
McCormick 1997 Methods
RCT Sepsis
Participants
128 adult patients with chronic liver disease (cirrhosis) and suspected or proven sepsis
Interventions
Ceftazidime 2grX2 for 5 days vs. mezlocillin 5grX3 + netilmicin 3mg/kgX2 for 4 days
Outcomes
Overall mortality Treatment failure (clinical) Adverse events Duration of treatment and hospital stay
Notes
Ireland Outcomes in subgroups: Bacteremia
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
49
Mergoni 1987 Methods
RCT Sepsis
Participants
Adult patients in ICU with severe infections
Interventions
Azlocillin 13+-2.2gr for 6.5 days vs. azloclillin 14.1+-1gr + amikacin 1.16+-0.027gr for 7.2 days (all in for daily doses)
Outcomes
Treatment failure (clinical and bacteriological) Adverse events Duration of treatment
Notes
Italy Outcomes in subgroups: Gram negative and Pseudomonas sp. infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Moreno 1997 Methods
RCT Sepsis
Participants
Renal or (kidneypancreas) transplant patients with fever and suspected bacterial infection
Interventions
Imipenem-cilastatin 500mgX4 vs. piperacillin 4grX3 + tobramycin 80mgX2
Outcomes
Treatment failure (clinical and bacteriological)
Notes
Spain Outcomes in subgroups: Gram negative and Pseudomonas sp. infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
50
Mouton 1990 Methods
RCT Sepsis
Participants
211 adult patients hospitalized in intensive care unit with respiratory tract infections
Interventions
Imipenem 500mgX4 for 11.1 days vs. cefotaxime 1grX4 + amikacin 5mg/kgX3 for 10.4 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfections Colonization Hospitalization duration Duration of treatment
Notes
Multicentre France (French) Outcomes in subgroups: Bacteremia
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Mouton 1995 Methods
RCT Sepsis
Participants
237 adult patients with community or hospital acquired serious infections, excluding intra-abdominal sepsis (urinary tract infection included)
Interventions
Meropenem 1grX3 for 8.8 days vs. ceftazidime 2grX3 + amikacin 5-7.5mg/kgX2-3 for 8.3 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfections Adverse events Dropouts Duration of treatment
Notes
Multicentre Europe Outcomes in subgroups: Bacteremia
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
51
Mouton 1995
(Continued) Gram negative and Pseudomonas sp. and urinary tract infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Muller 1987 Methods
RCT Abdominal
Participants
Trial includes 3 arms (2 monotherapies, 1 combination treatment) 106 patients evaluated with acute cholecystitis or cholangitis
Interventions
Piperacillin 3grX6 for 7.4 days vs. cefoperazone 2grX3 for 8.1 days vs. ampicillin 2grX4 + tobramycin 1-1.5mg/kgX3 following 1.5mg/kg loading dose for 11.1 days
Outcomes
Treatment failure (clinical) Adverse events Duration of treatment
Notes
Bi-centre USA No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Naime Libien 1992 Methods
RCT Sepsis
Participants
30 children aged 1m - 11yr with severe lower respiratory tract infections
Interventions
Ceftizoxime 20-50mg/kgX2-3 vs. penicillin 0.7-1.7 megaunit/kgX3 + gentamicin 1-1.5mg/kgX2
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
52
Naime Libien 1992
(Continued)
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Adverse events Duration of fever
Notes
Mexico (Spanish) No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Piccart 1984 Methods
RCT Sepsis
Participants
105 adult, non-neutropenic, cancer patients with suspected Gram-negative infections. Study included both neutropenic and non-neutropenic patients, but analysis was completely separated Patients with Gram-positive bacteremia were excluded
Interventions
Cefoperazone 6grX2 vs. cefoperazone 2grX2 + amikacin 500mgX2
Outcomes
Treatment failure (clinical and bacteriological) Superinfections (bacterial and fungal) Drop-outs after randomization
Notes
Belgium Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections Bacteremia
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
53
Rapp 1984 Methods
RCT Sepsis
Participants
35 adult patients hospitalized in a neurosurgical intensive care unit. All with nosocomial pneumonia
Interventions
Ceftazidime 2grX3 vs. ticarcillin 3grX4 + tobramycin pharmacokinetically adjusted doses after 1.75mg/kd loading dose
Outcomes
Treatment failure (clinical and bacteriological) Adverse events
Notes
USA Outcomes in subgroups: Gram negative bacteremia Pseudomonas sp. infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Rasmussen 1986 Methods
RCT Urinary tract infections
Participants
62 adult patients hospitalized in a urosurgical department with urinary tract infections, mostly postoperative
Interventions
Cefotaxime 3grX3 for 5.4 days vs. ampicillin 1grX4 + netilmicin 150mgX3 for 7 days
Outcomes
Treatment failure (clinical) Relapse Duration of fever and treatment Adverse events
Notes
Denmark Outcomes in subgroups: Urinary tract infections
Risk of bias Item
Authors’ judgement
Description
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
54
Rasmussen 1986
(Continued)
Allocation concealment?
Unclear
B - Unclear
Ribera 1996 Methods
RCT Semi-empirical Gram-positive infections
Participants
Spain 90 intravenous drug users randomized, of which 74 had Staphylococcus aureus right-sided endocarditis. 90.5% of patients were HIV positive. Diagnostic criteria for possible (13% of study patients), probable (34%) and definitive endocarditis (53%) are defined in study
Interventions
Cloxacillin 2grX6 vs. cloxacillin 2grX6 + gentamicin 1mg/kgX3
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Relapse, re-infection and need for surgery Duration of treatment Adverse events
Notes
Spain Journal publication. Outcomes in subgroups: Bacteremia
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Rubinstein 1995 Methods
RCT Sepsis
Participants
580 adult patients with serious hospital acquired infections and a diagnosis of sepsis, pneumonia or upper urinary tract infection
Interventions
Ceftazidime 2grX2 for 9 days vs. ceftriaxone 2grX1 + tobramycin 3-5mg/kgX1 following 2mg/kg loading dose for 9 days
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
55
Rubinstein 1995
(Continued)
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfections Duration of treatment Adverse events
Notes
Multicentre Europe, Middle East, Asia, South America Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections Bacteremia Urinary tract infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Sage 1987 Methods
RCT Sepsis
Participants
93 patients > 14yrs. randomized to 3 arms, of which 2 are usable in the review. The 3rd arm is aminoglycoside monotherapy. Patients were suspected of a life threatening sepsis, thought to be caused by Enterobacteriaceae or Staphylococci
Interventions
Cefotaxime 1-2grX4 for 7.4 days vs. cefotaxime 1-2grX4 + netilmicin 2-3mg/kgX3 (3rd arm, not used netilmicin 2-3mg/kgX3) for 8.7 days
Outcomes
Treatment failure (clinical and bacteriological) Bacterial and fungal superinfections Dropouts Adverse events Duration of treatment
Notes
UK Outcomes in subgroups: Bacteremia Gram negative and urinary tract infections
Risk of bias
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
56
Sage 1987
(Continued)
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Sandberg 1997 Methods
RCT Urinary tract infections
Participants
73 adult female patients with suspected pyelonephritis
Interventions
Cefotaxime 1grX2 for 2 days followed by oral cefadroxil 1grX2 vs. cefotaxime 1grX2 + tobramycin 160mgX1 for 2 days, followed by oral cefadroxil 1 grX2
Outcomes
Treatment failure (clinical and bacteriological) Superinfection and colonization (relapse, re-infections and asymptomatic bacteriuria recurrence) Adverse events Drop-outs after randomization Duration of fever
Notes
Multicentre Sweden Outcomes in subgroups: Urinary tract infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Sanfilippo 1989 Methods
RCT Abdominal
Participants
26 female patients aged 16-19 years with acute pelvic inflammatory disease
Interventions
Mezlocillin 62.5mg/kgX4 vs. penicillin 480,000U/kgX4 + tobramycin 1mg/kgX3
Outcomes
Treatment failure (clinical)
Notes
USA No outcomes in subgroups
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Sanfilippo 1989
(Continued)
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Sculier 1982 Methods
RCT Sepsis
Participants
20 adult, intubated, patients with Gram-negative pneumonia in the neurosurgical intensive-care unit Patients were randomized when presenting with radiographic bronchopneumonia, purulent sputum and Gram-negative rods on sputum direct smear
Interventions
Mezlocillin 10grX3 vs. mezlocillin 10grX3 + sisomicin 75mgX3. In addition to allocated systemic treatment, all patients received intra-tracheal sisomycin 25mgX3/d
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Bacterial colonization Resistance development Adverse events
Notes
Belgium Outcomes in subgroups: Gram negative and Pseudomonas sp. infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Sexton 1998 Methods
RCT Semi-empirical Gram-positive infections
Participants
67 adult patients randomized, of which 51 with native valve endocarditis (defined by Duke criteria) caused by penicillinsusceptible Streptococci.
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Sexton 1998
(Continued)
Interventions
Ceftriaxone 2grX1 for 4 weeks vs. ceftriaxone 2grX1 + gentamicin 3mg/kgX1 for 2 weeks
Outcomes
Treatment failure (clinical and bacteriological) Relapse and re-infection Adverse events Dropouts Duration of hospital stay Need for surgery
Notes
Multicentre USA Outcomes in subgroups: Bacteremia
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Sieger 1997 Methods
RCT Sepsis
Participants
211 adults >18yrs. with hospitalacquired lower respiratory tract infections. 70% intubated and 27% with severe pneumonia
Interventions
Meropenem 1grX3 for 7.8 days vs. ceftazidime 2grX3 + tobramycin 1mg/kgX3 (following 1.5-2mg/kg loading dose) for 7.4 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfections Adverse events Duration of treatment
Notes
Multicentre USA Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections. Study performs both efficacy and ITT analysis, with a drop-out rate of 43% for the efficacy analysis. Outcomes were extracted by ITT. Superinfections and subgroup analyses are given only by efficacy analysis in study
Risk of bias
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Sieger 1997
(Continued)
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Smith 1984 Methods
RCT Sepsis
Participants
200 adult patients randomized with suspected or proven serious infections. 195 who actually received study drugs were evaluated for efficacy
Interventions
Cefotaxime 2grX6 + placebo X3 for 5 days vs. nafcillin 1.5grX6 + tobramycin 2mg/kgX3 for 5.3 days (Addition of clindamycin 600mgX3 to both groups permitted for suspected anaerobic infections)
Outcomes
Overall mortality Treatment failure (clinical and microbiological) Bacterial superinfections Colonization Adverse events Duration of treatment
Notes
USA Outcomes in subgroups: Urinary tract and Gram negative infections. Two additional references refer to the same trial: Moore 1986a (cost-effectiveness analysis), and Moore 1986b (nephrotoxicity analysis). Overall mortality, and treatment duration are taken from Moore 1986a that analysed all patients given study drugs. Cost outcome not included in the review
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Speich 1998 Methods
RCT Sepsis
Participants
89 adults >16yrs. with severe pneumonia. Community acquired in 89%
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Speich 1998
(Continued)
Interventions
Piperacillin-tazobactam 4.5grX3 for 10.2 days vs. amoxicllin-clavulonic acid 2.2grX3 + gentamicin or netilmicin 3-6mg/kgX1 for 10.1 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Dropouts Adverse events Duration of treatment
Notes
Multicentre Switzerland No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Yes
A - Adequate
Stille 1992 Methods
RCT Sepsis
Participants
337 adult patients randomized with non-lifethreatening infections, of abdominal, gynaecological or respiratory tract origin (UTI, skin, bone, and CNS infections excluded)
Interventions
Imipenem 500mgX3 for 8.4 days vs. cefotaxime 2grX3 + gentamicin 0.66-1mg/kgX3 for 8.2 days (metronidazile allowed in combination treatment group for suspected anaerobic infection)
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Colonization and resistance development Adverse events Duration of treatment
Notes
Multicentre Germany and Austria Outcomes in subgroups: Gram negative and Pseudomonas sp. infections
Risk of bias
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Stille 1992
(Continued)
Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Sukoh 1994 Methods
RCT Sepsis
Participants
63 patients with respiratory tract infections and underlying respiratory disease
Interventions
Cefoperazone/ sulbactam 1-4gr/d for 11.7 days vs. Cefoperazone/ sulbactam 2-6gr/d + one of several aminoglycosides in low doses (amikacin 100-400 mg/d 16 patients, tobramycin 40-180 mg/d 15 patients, isepamicin 400 mg/d 1 patient, netilmicin 200 mg/d 1 patient) for 11.1 days
Outcomes
Treatment failure (clinical and bacteriological)
Notes
Japan (Japanese) Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Takamoto 1994 Methods
RCT Sepsis
Participants
171 adult patients with respiratory tract infections
Interventions
Imipenem/cilastatin sodium vs. imipenem/cilastatin sodium + amikacin sulfate
Outcomes
Treatment failure (clinical and bacteriological) Drop-outs after randomization Adverse events
Notes
Multicentre Japan (Japanese) Outcomes in subgroups: Gram-negative and Pseudomonas sp. infections
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Takamoto 1994
(Continued)
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Thompson 1990 Methods
RCT Abdominal
Participants
96 patients evaluated with acute cholangitis (cholecystitis not included)
Interventions
Piperacillin 3grX6 for 8.4 days vs. ampicillin 2grX4 + tobramycin 1-1.5mg/kgX3 for 9.1 days (following 1.5mg/kg loading dose). In addition 35/96 patients were operated on
Outcomes
Overall mortality Treatment failure (clinical) Adverse events Treatment duration
Notes
Multicentre USA No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Thompson 1993 Methods
RCT Abdominal
Participants
120 patients evaluated with acute biliary tract infections (cholecystitis and cholangitis)
Interventions
Cefepime 2grX2 for 7.5 days vs. mezlocillin 3grX6 + gentamicin 1.5mg/kgX3 for 7 days. In addition, 118/120 patients were operated on
Outcomes
Overall mortality Treatment failure (clinical) Adverse events
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Thompson 1993
(Continued) Treatment and hospitalization duration
Notes
Multicenter USA No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Trujillo 1992 Methods
RCT Sepsis
Participants
30 adult patients with severe skin and soft tissue or respiratory tract infections
Interventions
Ceftizoxime 1-2grX3 vs. ampicillin 1-3grX4 + gentamicin 3-5mg/kg/d, overall for 10 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Adverse events Fever duration
Notes
Mexico (Spanish) No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Vergnon 1985 Methods
RCT Sepsis
Participants
30 adult patients wth severe bronchopulmonary infections
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Vergnon 1985
(Continued)
Interventions
Cefoperazone 2grX2 for 16.8 days vs. ampicillin 1.5grX4 + tobramycin 1mg/kgX3 for 11.8 days
Outcomes
Treatment failure (clinical) Resistant colonization Adverse events Duration of treatment
Notes
France (French) No outcomes in subgroups
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Verzasconi 1995 Methods
RCT Urinary tract infections
Participants
93 adult patients with acute pyelonphritis or complicated urinary tract infections
Interventions
Amoxicillin-clavulonate 2.2grX3 for 4.1 days vs. amoxicillin 2grX3 + gentamicin 1.5mg/kg loading followed by maintenance for 4.2 days
Outcomes
Treatment failure (bacteriological) Superinfection Dropouts Treatment and fever duration Adverse events
Notes
Bi-centre Switzerland (German) Outcomes in subgroups: Urinary tract infection
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Warren 1983 Methods
RCT Sepsis
Participants
120 adult patients with suspected or known life-threatening infections caused by Gram-negative bacilli
Interventions
Cefoperazone 1.5grX4 for a median of 9 days vs. cefamandole 2grX6 + tobramycin 1.7mg/kg loading dose, followed by drug- level-adjusted maintenance dose for a median of 8 days
Outcomes
Overall mortality Treatment failure (clinical and bacteriological) Superinfection Duration of treatment Adverse events Drop-outs after randomization
Notes
USA Outcomes in subgroups: Bacteremia Gram-negative infections
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Wiecek 1986 Methods
RCT Urinary tract infections
Participants
20 adult patient with acute pyelonphritis
Interventions
Ceftazidime 1grX3 vs. cefotaxime 1grX2 + tobramycin 1mg/kgX3
Outcomes
Treatment failure (bacteriological) Re-infection Adverse events
Notes
Poland Outcomes in subgroups: Gram negative and Pseudomonas sp. infections Urinary tract infections
Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Wiecek 1986
(Continued) Bacteremia
Risk of bias Item
Authors’ judgement
Description
Allocation concealment?
Unclear
B - Unclear
Wing 1998 Methods
RCT Urinary tract infections
Participants
179 pregnant women